Method and system for manufacturing and oral soluble films and oral soluble films made by thereby

ABSTRACT

An oral soluble film contains at least one active agent. Alternatively, a multi-layered film includes a plurality of layers, at least one at least one of the plurality of layers being an oral soluble film layer containing at least one active agent. The oral soluble film may be made, e.g., by a method comprising providing a well of a predetermined size; depositing a film forming composition in the well; metering a predetermined amount of an active agent composition in the well separately from the film forming composition, the active agent composition being different than the film forming composition, the film forming composition and the active agent composition forming a single layer in the well; and drying the single layer in the well to form the oral soluble film containing the at least one active agent.

CROSS-REFERENCE TO RELATED APPLICATION

This application discloses improvements to the subject matter describedin, inter alia, U.S. patent application Ser. No. 15/486,331, filed Apr.13, 2017, now U.S. Pat. No. 9,901,545; Ser. No. 15/866,729, filed Jan.10, 2018, now U.S. Pat. No. 10,195,142; and Ser. No. 16/703,992, filedDec. 5, 2019, the contents of each of which are incorporated herein intheir entireties.

BACKGROUND OF THE INVENTION

Active ingredients, such as but not limited to drugs or pharmaceuticals,may be prepared in a tablet form to allow for accurate and consistentdosing. However, this form of preparing and dispensing medications hasmany disadvantages perhaps a very significant example is the need for agranulation step in most tablets which can be destructive to certainbioactives such as but not limited to, vaccines, sensitives drugs etc.but also make the use of very low dosage units quite difficult becauseof the dilutive and mixing steps, also including a large proportion ofadjuvants that must be added to obtain a size able to be handled, that alarger medication form requires additional storage space, and thatdispensing includes counting the tablets which has a tendency forinaccuracy. In addition, many persons, estimated to be as much as 28% ofthe population, have difficulty swallowing tablets and perhaps a higherpercentage have a perceived difficulty of same.

While tablets may be broken into smaller pieces or even crushed as ameans of overcoming swallowing difficulties, this is not a suitablesolution for many tablet or pill forms. For example, crushing ordestroying the tablet or pill form to facilitate ingestion, alone or inadmixture with food, may also destroy the controlled release properties,taste masking properties, or otherwise effect the pharmacokineticproperties of the drug.

As an alternative to tablets and pills, films may be used to carryactive ingredients such as drugs, pharmaceuticals, dermals,cosmeceuticals, botanicals and the like.

However, historically films and the process of making drug deliverysystems therefrom have suffered from a number of unfavorablecharacteristics, and the industry struggled to develop a commerciallyviable way to manufacture films for consumers.

Films that incorporate a pharmaceutically active ingredient aredisclosed in expired U.S. Pat. No. 4,136,145 to Fuchs, et al. (“Fuchs”)(hereby incorporated by reference as if fully set forth). These filmsmay be formed into a sheet, dried and then cut into individual doses.The Fuchs disclosure alleges the fabrication of a uniform film, whichincludes the combination of water-soluble polymers, surfactants,flavors, sweeteners, plasticizers and drugs. These allegedly flexiblefilms are disclosed as being useful for oral, topical or enteral use.Examples of specific uses disclosed by Fuchs include application of thefilms to mucosal membrane areas of the body, including the mouth,rectal, vaginal, nasal and otic areas.

Commentators have suggested that examination of films made in accordancewith the process disclosed in Fuchs, however, reveals that such filmssuffer from the aggregation or conglomeration of particles, i.e.,self-aggregation, making them inherently non-uniform. See U.S. Pat. No.8,658,437 (Yang et al., including the instant applicants) (herebyincorporated by reference as if fully set forth) discussing Fuchs.

The formation of agglomerates randomly distributes the film componentsand any active present as well. When large dosages are involved, a smallchange in the dimensions of the film would lead to a large difference inthe amount of active per film. If such films were to include low dosagesof active, it is possible that portions of the film may be substantiallydevoid of any active.

What constitutes true uniformity in a cast film? It is usually not atrue molecular uniformity but rather a dispersion of active in which agiven size film falls within generally accepted guidelines. In otherinstances, it may involve molecular uniformity, either measured forspecific geographies, or within the film layer or layers themselves,this is substantially limited to active agents that are totally solublein the film matrix.

Since sheets of film are usually cut into unit doses, certain doses maytherefore be devoid of or contain an insufficient amount of active forthe recommended treatment. Failure to achieve a high degree of accuracywith respect to the amount of active ingredient in the cut film can beharmful to the patient. For this reason, dosage forms formed byprocesses such as Fuchs, would not likely meet the stringent standardsof governmental or regulatory agencies, such as the U.S. Federal DrugAdministration (“FDA”), relating to the variation of active in dosageforms.

Currently, as required by various world regulatory authorities, dosageforms may not vary more than 10% in the amount of active present. Whenapplied to dosage units based on films, this virtually mandates thatuniformity of the drug in the film be present. As a practical matter,stricter tolerances may be required by individual manufacturers, e.g.vary not more than 5%. In addition, there is a direct relationship todosage size and as dosage size decreases this challenge increases.

The problems of self-aggregation leading to non-uniformity of a filmwere addressed in U.S. Pat. No. 4,849,246 to Schmidt (“Schmidt”) (herebyincorporated as if fully set forth). Schmidt specifically pointed outthat the methods disclosed by Fuchs did not provide a uniform film andrecognized that that the creation of a non-uniform film necessarilyprevents accurate dosing, which as discussed above is especiallyimportant in the pharmaceutical area.

Schmidt abandoned the idea that a mono-layer film, such as described byFuchs, may provide an accurate dosage form and instead attempted tosolve this problem by forming a multi-layered film. Schmidt forms aninitial water-soluble wet cast film. Next, “an aqueous coating materialis prepared from the active ingredient, as well as starches, gelatins,glycerol and/or sorbitol, as well as optionally natural and/or syntheticresins and/or gums, and . . . the coating material is continuouslyapplied by means of a roll coating process and in a preciselypredetermined quantity (i.e. via coating thickness) to at least one sideof the support film . . . . With the aid of modern roll applicationprocesses the active ingredient-containing coating can be applied with aconstant thickness, so that the necessary tolerances can be respected.”

The Schmidt process is a multi-step process that adds expense andcomplexity and is not practical for commercial use and is in fact nomore a guarantee of uniformity than is Fuchs. In fact, the Schmidtpatent has expired without, to the personal knowledge of the instantinventors, any commercial use. Yang et al describe a related approach,wherein, in a cast film, “particles or particulates may be added to thefilm-forming composition or matrix after the composition or matrix iscast into a film. For example, particles may be added to the film 42prior to the drying of the film 42. Particles may be controllablymetered to the film and disposed onto the film through a suitabletechnique, such as through the use of a doctor blade (not shown) whichis a device which marginally or softly touches the surface of the filmand controllably disposes the particles onto the film surface” (U.S.Pat. No. 9,108,340) (hereby incorporated by reference as if fully setforth).

Other U.S. patents directly addressed the problems of particleself-aggregation and non-uniformity inherent in conventional filmforming techniques.

U.S. Pat. No. 5,629,003 to Horstmann et al. and U.S. Pat. No. 5,948,430to Zerbe et al. (each, hereby incorporated by reference as if fully setforth) incorporated additional ingredients, i.e. gel formers andpolyhydric alcohols in wet cast films, respectively, to increase theviscosity of the film prior to drying.

In addition to the concerns associated with degradation of an activeduring extended exposure to moisture, the conventional drying methodsthemselves may be unable to provide uniform films.

The length of heat exposure during conventional processing, oftenreferred to as the “heat history”, and the manner in which such heat isapplied, have a direct effect on the formation and morphology of theresultant film product.

Uniformity is particularly difficult to achieve via conventional dryingmethods where a relatively thicker film, which is well-suited for theincorporation of a drug active, is desired. Thicker uniform films aremore difficult to achieve because the surfaces of the film and the innerportions of the film do not experience the same external conditionssimultaneously during drying.

Thus, according to commentators (U.S. Pat. No. 7,425,292) (herebyincorporated by reference as if fully set forth), observation ofrelatively thick films made from such conventional processing shows anon-uniform structure caused by convection and intermolecular forces andmay require moisture to remain flexible. The amount of free moisture canoften interfere over time with the drug leading to potency issues andtherefore inconsistency in the final product.

Put simply, the practitioner may walk a tightrope between moistureneeded for desired mechanical attributes (flexibility of theself-supported film), and potentially deleterious consequences forchemical stability of the active ingredient associated with moisture.

Some discussion of mechanical attributes is important. In a conventionalwet cast film at the large manufacturing scale, the film is coated on toan inert flexible substrate, dried, then rolled (wound) onto itself. Thefilm is then transported to the next discrete processing step where itis unrolled (unwound) and then processed to make it suitable fortransport and handling. Typically, the edges are removed (trimmed, withloss of active), and the web (width) is cut into narrower-width sections(typically called “slitting”) that can be accommodated by the filmpackaging machine (typically called “conversion” of the film). The filmis then re-rolled (re-wound) upon itself after slitting and may or maynot have been removed from its coating substrate, but either wayrequires sufficient mechanical strength to accommodate this processing.

If films lack the requisite pliability and tensile strength, they willtend to break during packaging causing substantial losses in processyield. Such breakage issues presumably led to the filing of a patent onmethods of film splicing by Novartis (Slominski et al US 20060207721A1). Some pliable, strong wet cast films use polyethylene oxide (PEO)based compositions (See Yang et al. US 2005/0037055 A1) (herebyincorporated by reference as if fully set forth). The strength of thesefilms has led to the subsequent use of PEO in formulations commerciallysold by Novartis. The reality is that physical strength and resultingbreakage and process yield issues caused by breakage have beensignificant problems for many of the wet cast films.

However, as regards pliability, again the practitioner walks atightrope. If the film is too pliable (ductile or rubbery), it maystretch (elongate), particularly in the packaging stage where the filmis under tension in the packaging lanes. Typically, in film packaging(conversion), the sub-roll of film is slit into lanes (each lanerepresenting the width of the final dose) and then processed into unitdose foil packages. The final dosage is premised on relatively uniformtotal distribution of drug in the individual film, and then cuttingequally dimensioned pieces of films based on the calculated drugconcentration. Hopefully that concentration is known ex ante (beforecoating), but it can also be determined ex post (after coating).

However, if the film is too pliable, it may stretch under tension (mostcommonly in the packaging stage here). The effect of such stretchingwill decrease the concentration of the drug in the film. For a“stretched” film, the given calculated dimensions (that did notanticipate stretch/elongation) will now yield an under-strength dosageform.

As a result, the formulator must provide a film that, when dried, issufficiently pliable to accommodate conversion (and not, say, breakunder tension). At the same time, the film cannot be too pliable or itwill stretch

Even if the film's mechanical properties are sufficient for conversionand packaging, physical stability of the final dosage form over time isnot necessarily assured.

The issue of physical stability is also an issue for wet castfilms—expensive barrier packaging is often used as a matter ofnecessity. Still, physical stability is not always a given. BootsChemists launched a Vitamin C strip manufactured by BioProgress in TampaFla. that had to be removed from the shelves because it was crumbling inthe package—earning the name “chips not strips.”

This story is not unique—many projects have failed to move out fromdevelopment to commercialization due to physical stability issues.

The formulator must accommodate these needs while still achieving therequired performance when used (e.g. desired disintegration time,desired muco-adhesion if a buccal film, desired solid state of the drugetc.).

Conventional drying methods generally include the use of forced hot airusing a drying oven, drying tunnel, and the like. The difficulty inachieving a uniform film is directly related to the rheologicalproperties and the process of solvent evaporation in the film-formingcomposition as well as but not limited to the matters described above.

When the surface of a polymer solution is contacted with a hightemperature air current, such as a film-forming composition passingthrough a hot air oven, the surface solvent is immediately evaporatedand theoretically forms a polymer film or skin on the surface. This canseal the remainder of the film-forming composition beneath the surface,forming a barrier through which the remaining solvent must force itselfas it is evaporated in order to achieve a dried film. As the temperatureoutside the film continues to increase, vapor pressure builds up underthe surface of the film, stretching the surface of the film, andultimately ripping the film surface open allowing the solvent to escape.As soon as the solvent has escaped, the polymer film surface reforms,and this process is repeated, until the film is completely dried. Theresult of the repeated destruction and reformation of the film surfaceis observed as a “ripple effect” which produces an uneven, and oftennon-uniform film. Frequently, depending on the polymer, a surface willseal so tightly that the remaining water is difficult to remove, leadingto very long drying times, higher temperatures, and higher energy costs.

Other factors, such as mixing techniques, also play a role in themanufacture of a pharmaceutical film, particularly a wet cast film,suitable for commercialization and regulatory approval. Air can betrapped in the composition during the mixing process or later during thefilm making process, which can leave voids in the film product as themoisture evaporates during the drying stage. The film may collapsearound the voids resulting in an uneven film surface and therefore,non-uniformity of the final film product. Uniformity is still affectedeven if the voids in the film caused by air bubbles do not collapse.This situation also provides a non-uniform film in that the spaces,which are not uniformly distributed, are occupying area that wouldotherwise be occupied by the film composition and more importantlybecause there is a single mix in prior art casting, voids mean “noactive present” here.

Some discussion of coating methods is needed, and the present inventorsprovide a good primer in U.S. Pat. No. 7,824,588 (Yang et al includingthe present inventors) (hereby incorporated by reference as if fully setforth):

“Coating or casting methods are particularly useful for the purpose offorming the films of the present invention. Specific examples includereverse roll coating, gravure coating, immersion or dip coating,metering rod or meyer bar coating, slot die or extrusion coating, gap orknife over roll coating, air knife coating; curtain coating, orcombinations thereof, especially when a multi-layered film is desired.In this procedure, the coating material is measured onto the applicatorroller by the precision setting of the gap between the upper meteringroller and the application roller below it. The coating is transferredfrom the application roller to the substrate as it passes around thesupport roller adjacent to the application roller. Both three roll andfour roll processes are common.”

“The gravure coating process relies on an engraved roller running in acoating bath, which fills the engraved dots or lines of the roller withthe coating material. The excess coating on the roller is wiped off by adoctor blade and the coating is then deposited onto the substrate as itpasses between the engraved roller and a pressure roller.”

“Offset Gravure is common, where the coating is deposited on anintermediate roller before transfer to the substrate.”

“In the simple process of immersion or dip coating, the substrate isdipped into a bath of the coating, which is normally of a low viscosityto enable the coating to run back into the bath as the substrateemerges.”

“In the metering rod coating process, an excess of the coating isdeposited onto the substrate as it passes over the bath roller. Thewire-wound metering [bar], sometimes known as a Meyer [Rod], allows thedesired quantity of the coating to remain on the substrate. The quantityis determined by the diameter of the wire used on the rod.”

“In the slot die process, the coating is squeezed out by gravity orunder pressure through a slot and onto the substrate. If the coating is[substantially or 100% solid material (i.e. very low solvent or nosolvent use)], the process is termed ‘Extrusion.’”

The '588 continues: “The gap or knife over roll process relies on acoating being applied to the substrate which then passes through a ‘gap’between a ‘knife’ and a support roller. As the coating and substratepass through, the excess is scraped off. Air knife coating is where thecoating is applied to the substrate and the excess is ‘blown off’ by apowerful jet from the air knife. This procedure is useful for aqueouscoatings. In the curtain coating process, a bath with a slot in the baseallows a continuous curtain of the coating to fall into the gap betweentwo conveyors. The object to be coated is passed along the conveyor at acontrolled speed and so receives the coating on its upper face.”

Yang et al, including the present inventors, teach a “selection of apolymer or combination of polymers that will provide a desiredviscosity, a film-forming process such as reverse roll coating, and acontrolled, and desirably rapid, drying process which serves to maintainthe uniform distribution of non-self-aggregated components without thenecessary addition of gel formers or polyhydric alcohols.” See U.S. Pat.No. 9,108,340 (hereby incorporated by reference as if fully set forth).

Yang et al. strongly rely on viscosity in the pre-cast film solution tomaintain drug content uniformity, and on said viscoelastic properties ofthe film composition to retard and avoid excess migration of drug duringboth the casting and drying process.

As U.S. Pat. No. 8,603,514 (Yang et al.) (hereby incorporated byreference as if fully set forth) describes: “the viscosity of the liquidphase is critical and is desirably modified by customizing the liquidcomposition to a viscoelastic non-Newtonian fluid with low yield stressvalues. This is the equivalent of producing a high viscosity continuousphase at rest. Formation of a viscoelastic or a highly structured fluidphase provides additional resistive forces to particle sedimentation.Further, flocculation or aggregation can be controlled minimizingparticle-particle interactions.

The net effect would be the preservation of a homogeneous dispersedphase.”

Yang et al. invoke Stokes' law to support this high viscosity approach.U.S. Pat. No. 8,603,514 describes: “One approach provided by the presentinvention is to balance the density of the particulate (ρ_(p)) and theliquid phase (pi) and increase the viscosity of the liquid phase(μ). Foran isolated particle, Stokes law relates the terminal settling velocity(Vo) of a rigid spherical body of radius (r) in a viscous fluid, asfollows: V_(o)=(2gr^(r))(ρ_(p)−ρ₁)/9μ”

Accordingly, claim 1 of U.S. Pat. No. 8,603,514 requires, inter alia,the following element concerning the viscosity of the film formingmatrix: “matrix has a viscosity sufficient to aid in substantiallymaintaining non-self-aggregating uniformity of the active in thematrix.”

The film compositions of Yang et al. (and other film artisans citedabove) are so viscous that mechanical means (i.e. a physicalmeans/physical object) in contact with the composition) are required toform a film by spreading the film composition on to the substrate. Putsimply, the compositions are too viscous and have surface tension thatis too high to pour. This is helpful in the coating process; after all,if the composition were too flowable it would roll/flow off thesubstrate. U.S. Pat. No. 8,906,277 (Yang et al.) (hereby incorporated byreference as if fully set forth) describes the ability of the mechanicalcoating apparatus as providing the upper limit on viscosity of the filmformulation: “the viscosity must not be too great as to hinder orprevent the chosen method of casting, which desirably includes reverseroll coating due to its ability to provide a film of substantiallyconsistent thickness.”

After the Yang et al. film compositions have been coated, Yang et al.describe a controlled drying process to avoid agglomeration of drug andresultant loss of content uniformity.

U.S. Pat. No. 8,603,514 (Yang et al.) describes: “In conventional ovendrying methods, as the moisture trapped inside subsequently evaporates,the top surface is altered by being ripped open and then reformed. Thesecomplications are avoided by the present invention, and a uniform filmis provided by drying the bottom surface of the film first or otherwisepreventing the formation of polymer film formation (skin) on the topsurface of the film prior to drying the depth of the film. This may beachieved by applying heat to the bottom surface of the film withsubstantially no top air flow, or alternatively by the introduction ofcontrolled microwaves to evaporate the water or other polar solventwithin the film, again with substantially no top air flow. Yetalternatively, drying may be achieved by using balanced fluid flow, suchas balanced air flow, where the bottom and top air flows are controlledto provide a uniform film. In such a case, the air flow directed at thetop of the film should not create a condition which would cause movementof particles present in the wet film, due to forces generated by the aircurrents. Additionally, air currents directed at the bottom of the filmshould desirably be controlled such that the film does not lift up dueto forces from the air. Uncontrolled air currents, either above or belowthe film, can create non-uniformity in the final film products. Thehumidity level of the area surrounding the top surface may also beappropriately adjusted to prevent premature closure or skinning of thepolymer surface.”

“This manner of drying the films provides several advantages. Amongthese are the faster drying times and a more uniform surface of thefilm, as well as uniform distribution of components for any given areain the film. In addition, the faster drying time allows viscosity toquickly build within the film, further encouraging a uniformdistribution of components and decrease in aggregation of components inthe final film product.”

High viscosity, high surface tension, and difficult flowability is agiven in coating line systems. The picture at this link shows(www.matik.com/olbrich-answers-the-call-from-customers/) a standardOlbrich coating line. Olbrich is a leading manufacturer of coatingequipment. The coating apparatus is physically below the drying tunnel,with the freshly coated substrate taking off at a severe (high) anglegoing up to the drying tunnel. When before any drying, it is necessarythat the freshly coated film will not roll or flow off the substratedespite gravitational forces associated with this take off angle. It isimportant to note that drying methodology here is essential touniformity. In the invention to be described here, the dose unit isconfined and the drying method has substantially no role in dosageuniformity.

The Yang et al. approach has proved dominant in the marketplace forfilm. The most successful commercial orally soluble film product(measured by sales) is Suboxone® thin film, which has exceeded onebillion in US sales in certain years. The FDA Orange Book references twopatents of Yang and the present inventors in connection with Suboxone:U.S. Pat. Nos. 8,017,150 and 8,603,514. A third patent listed in theOrange Book for this product—U.S. Pat. No. 8,475,832 which deals with pHissues specific to Suboxone (as distinct from wet cast film manufacturegenerally)—has been found invalid by the District Court for Delaware(although this '832 pH patent may be under further judicial appeal).

To date, several sophisticated ANDA filers, including WatsonPharmaceuticals, TEVA Pharmaceuticals (the world's largest genericcompany with revenues exceeding twenty billion dollars) and PARPharmaceuticals, have been unable in judicial proceedings to shownon-infringement (or invalidity) of the Suboxone-Orange Book listedpatents.

The next largest commercial orally soluble film success is theacquisition by Sunovion of Cynapsus for $624 million USD to acquireCynapsus’ apomorphine sublingual film. Cynapsus has a licensingarrangement to the same patent estate as Suboxone according to publiclyavailable information(globenewswire.com/news-release/2016/04/04/825387/0/en/Cynapsus-Therapeutics-and-MonoSol-Rx-Announce-Global-IP-Licensing-Agreement.html).Moreover, the owner of the same patent estate recently sued BioDeliverySciences for patent infringement for its Belbuca™ product, claiminginfringement of another progeny of the same patent estate, U.S. Pat. No.8,765,167 (Yang et al).

The applicants are not aware of any orally soluble film product withsignificant sales that does not license this patent estate.

The subject of loss (yield) and wet casting must be addressed. As wehave discussed, wet cast film compositions are very viscous in theinitial mixing stage. This viscosity, together with high surfacetension, means that the film composition will experience loss withadhered product in the mixing apparatus and tubing from the mixingapparatus to the coater. Some mild loss may occur on the coatingapparatus itself. There will be initial loss of product to bring thecoater online until the product is running at standard parameters.Similarly, there will be loss at the end of a run bringing the coateroffline (i.e. when too little material remains to maintain the coaterrunning at standard parameters). As discussed, supra, product will belost in the conversion stage by edge trimming, as well as cases wherethe width of usable web does not evenly divide by the input widthrequired by the packaging line.

The packaging machine must be brought online (and offline at the end ofa run), necessitating waste. Any breakage of film during packaging willresult in waste in connection with lost product and restarting of theline. And so on—this is not a non-limitative list, but offers someinsight into the innate wastefulness of the process

The fact is that yields of wet cast film products are low, can result insubstantial product loss, which is particularly concerning when castingexpensive active pharmaceutical ingredients (API) (excipients beingrelatively inexpensive by comparison to API). Loss can be higher than25% of API, high as 35% API and even approaching 50% API loss. Such APIloss may be acceptable for high value branded targets, but ultimatelyrestricts the success of oral soluble film in competitive Rx, OTC andother consumer fields.

The oral soluble film format is generally preferred by consumers overorally disintegrating tablets, but the latter is currently lessexpensive to make (as compared with wet cast films). For example,generic ondansetron orally disintegrating tablets sell for $8/dose(www.drugs.com/price-guide/ondansetron#oral-tablet-disintegrating-4-mg);whereas ondansetron orally soluble film has a retail price of $35/dose(www.drugs.com/price-guide/zuplenz). In an era when drug prices areunder fire publicly, and third-party payers take a hard pencil toformulary reimbursement rates, this is a hard price differential tosupport. For orally soluble film to help deliver value to more patients,a more cost-effective method of film manufacture is needed.

One way to avoid some of the product loss associated with wet casting ishot melt extrusion. Insofar as an extruder acts as a mixer and typicallystarts with substantially dry, non-aqueous compositions, hot meltextrusion avoids mixing loss associated with wet casting.

One of the present applicants has two US patents dealing with hot meltextrusion products and methods: U.S. Pat. No. 9,125,434 (Fuisz) (herebyincorporated by reference as if fully set forth) and U.S. Pat. No.8,613,285 (Fuisz) (hereby incorporated by reference as if fully setforth). Hot melt extrusion offers other advantages including a muchsmaller manufacturing footprint than a wet casting line, and the abilityto make longer lasting films/sheets than can be made with wet casting.However, hot melt extrusion as a process has its own limitations (vis avis wet casting). A principal limitation of hot melt extrusion is asmaller menu of film formers that readily extrude, which makesformulation far more challenging (as compared with wet casting). Tastemasking and controlled release and incorporation of heat-labile activeingredients may also be harder. Heat stability of the activepharmaceutical ingredient may also be an issue. Despite its strengths,applicants are not aware of any significant commercial film product madeusing hot melt extrusion, and applicants believe that the smaller menuof available film formers is a reason for this.

Discussion of the Zydis system is appropriate. The Zydis system is anorally disintegrating tablet, and is classified by the FDA as such (asdistinct from orally soluble film). The Zydis system is well regardedfor its rapid disintegration (relative to other orally disintegratingtablets), though the system has some limitations in terms of drugloading, taste masking and fragility. A primer on the history of orallydisintegrating tablets, including reference to one of the presentinventors, is available here: en.wikipedia.org/wiki/Orallydisintegrating tablet.

The Zydis system, which is a freeze-dried tablet, is described in U.S.Pat. Nos. 4,371,516; 4,305,502; 4,758,598; 4,754,597, and 5,631,023, theteachings of all of which are incorporated herein by reference as iffully herein stated. The Zydis manufacturing method uses a pre-preparedliquid composition including a solvent, a granular therapeutic agent,and a gelatin containing carrier material.

The liquid composition (including the drug) is placed into one or moreshaped depressions in a tray or mold to define liquid composition filleddepressions. The liquid composition in the filled depressions is frozen,then the liquid portion of the liquid composition sublimed to define asolid medicament tablet. Sublimation is accomplished by freeze dryingand can take several days. Thus, the tablet manufacturing process is notcontinuous; Zydis tablets-in-sublimation are stored in racks in aspecial chamber for sublimation. Only after sublimation can they bepackaged.

Some mention of the CIMA orally disintegrating tablet is appropriate.The CIMA tablet uses a base-acid reaction (effervescence) to effect oraltablet disintegration. There is some support for the proposition thateffervescence enhances buccal absorption. See U.S. Pat. No. 6,200,604which is hereby incorporated by reference. Applicants are aware of nocommercial oral soluble film product with effervescence, and attributethis to the practical difficulties of including acid and base in a wetcast film composition (without the product prematurely effervescing).

Finally, some mention of three-dimensional printing is warranted. 3Dprinting has garnered much attention as a possible method formanufacturing pharmaceutical dosage forms. The products are printedlayer by layer (using binding materials in between the layers of powderto adhere powder one layer to the other). The reality has failed to meetthe hype, although a single printed dose product approval was obtainedby Aprecia Pharmaceuticals for a product using its Zipdose technologylicensed from MIT.

Applicants hereby incorporate by reference their oral film prior patentsas if fully stated herein—these include: U.S. Pat. No. 7,425,292 (Thinfilm with non-self-aggregating uniform heterogeneity and drug deliverysystems made therefrom); U.S. Pat. No. 7,666,337 (Polyethyleneoxide-based films and drug delivery systems made therefrom); U.S. Pat.No. 7,824,588 (Method of making self-supporting therapeuticactive-containing film); U.S. Pat. No. 7,897,080 (Polyethylene-oxidebased films and drug delivery systems made therefrom); U.S. Pat. No.7,972,618 (Edible water-soluble film containing a foam reducingflavoring agent); U.S. Pat. No. 8,017,150 (Polyethylene oxide-basedfilms and drug delivery systems made therefrom); U.S. Pat. No. 8,568,777(Packaged film dosage unit containing a complexate); U.S. Pat. No.8,603,514 (Uniform films for rapid dissolve dosage form incorporatingtaste-masking compositions); U.S. Pat. No. 8,613,285 (Extrudable andextruded compositions for delivery of bioactive agents, method of makingsame and method of using same); U.S. Pat. No. 8,617,589 (Biocompatiblefilm with variable cross-sectional properties); U.S. Pat. No. 8,652,378(Uniform films for rapid dissolve dosage form incorporatingtaste-masking compositions); U.S. Pat. No. 8,663,687 (Film compositionsfor delivery of actives); U.S. Pat. No. 8,685,437 (Thin film withnon-self-aggregating uniform heterogeneity and drug delivery systemsmade therefrom); U.S. Pat. No. 8,900,498 (Process for manufacturing aresulting multi-layer pharmaceutical film); U.S. Pat. No. 8,906,277(Process for manufacturing a resulting pharmaceutical film); U.S. Pat.No. 9,108,340 (Process for manufacturing a resulting multi-layerpharmaceutical film); U.S. Pat. No. 9,125,434 (Smokeless tobaccoproduct, smokeless tobacco product in the form of a sheet, extrudabletobacco composition); U.S. Pat. No. 9,150,341 (Unit assembly and methodof making same); U.S. Pat. No. 9,901,545 (Method and Composition formaking an oral soluble film, containing at least one active agent); U.S.Pat. No. 10,111,810 (Thin film with non-self-aggregating uniformheterogeneity and drug delivery systems made therefrom); U.S. Pat. No.10,195,142 (Method and composition for making an oral soluble film,containing at least one active agent); U.S. Pat. No. 10,238,600(Package, system and methods for custody and control of drugs); U.S.Pat. No. 10,285,910 (Sublingual and buccal film compositions); and U.S.Pat. No. 10,335,872 (Smokeless tobacco product, smokeless tobaccoproduct in the form of a sheet).

SUMMARY OF THE INVENTION

One aspect of the invention relates to an oral soluble film containingat least one active agent, the oral soluble film being made by a methodcomprising providing a well of a predetermined size; depositing a filmforming composition in the well; metering a predetermined amount of anactive agent composition in the well separately from the film formingcomposition, the active agent composition being different than the filmforming composition, the film forming composition and the active agentcomposition forming a single layer in the well; and drying the singlelayer in the well to form the oral soluble film containing the at leastone active agent.

Another aspect of the invention relates to an oral soluble filmcontaining at least one active agent, the oral soluble film being madeby a method comprising continuously stirring a suspension of a filmforming composition and particulates of at least one active agent in atank; depositing the suspension of the film forming composition and theparticulates of the at least one active agent separately into each of aplurality of wells while continuously stirring the suspension in thetank, the suspension of the film forming composition and theparticulates of the at least one active agent having a yield stress ofless than 30 Pa and forming a contact angle with the well of less than90°, wherein the suspension of the film forming composition and theparticulates of the at least one active agent flows into a film in thewell within 20 seconds and has a viscosity below 600 centipoise; anddrying the film using hot air currents to form the oral soluble filmcontaining the at least one active agent.

One aspect of the invention relates to an oral soluble film containingat least one active agent, the oral soluble film being made by a methodcomprising providing a well of a predetermined size; depositing a filmforming composition which also contains an active agent dissolved withinit, in the well; the film forming composition and the active agentcomposition forming a single layer in the well; and drying the singlelayer in the well to form the oral soluble film containing the at leastone active agent.

One aspect of the invention relates to an oral soluble film containingat least one active agent, the oral soluble film being made by a methodcomprising providing a well of a predetermined size; depositing a filmforming composition which also contains an active agent suspended withinit, in the well; the film forming composition and the active agentcomposition forming a single layer in the well; and drying the singlelayer in the well to form the oral soluble film containing the at leastone active agent.

Another aspect of the invention relates to an oral soluble filmcontaining at least one active agent, the oral soluble film being madeby a method comprising a film forming composition and at least onedissolved active agent within the film forming composition; depositingthe solution of the film forming composition and the dissolved activeagent together into each of a plurality of wells without stirring,having a yield stress of less than 30 Pa and forming a contact anglewith the well of less than 90°, wherein the solution of the film formingcomposition and the at least one active agent flows into a film in thewell within 20 seconds and has a viscosity below 600 centipoise; anddrying the film using hot air currents to form the oral soluble filmcontaining the at least one active agent.

In another aspect, the invention relates to a multi-layered filmcomprising a plurality of layers, at least one of the plurality oflayers being an oral soluble film layer containing at least one activeagent, the at least one oral soluble film layer being made by a methodcomprising providing a well of a predetermined size; depositing a filmforming composition in the well; metering a predetermined amount of anactive agent composition in the well separately from the film formingcomposition, the active agent composition being different than the filmforming composition, the film forming composition and the active agentcomposition forming a single layer in the well; and drying the singlelayer in the well to form the at least one oral soluble film layercontaining the at least one active agent. The multi-layered may includean insoluble backing layer. The multi-layered film may include asemi-insoluble backing layer. The multi-layered film may have multiplelayers each with a different active agent. The multi-layered compositionmay have a mucoadhesive layer and a barrier or backing layer. Themulti-layered composition may have a mucoadhesive gelling layer and abarrier or backing layer. The multi-layered composition may have athermo-reversible gelling layer and a barrier or backing layer.

In another aspect, the invention relates to a multi-layered filmcomprising a plurality of layers, at least one at least one of theplurality of layers being an oral soluble film layer containing at leastone active agent, the oral soluble film layer being made by a methodcomprising continuously stirring a suspension of a film formingcomposition and particulates of at least one active agent in a tank;depositing the suspension of the film forming composition and theparticulates of the at least one active agent separately into each of aplurality of wells while continuously stirring the suspension in thetank, the suspension of the film forming composition and theparticulates of the at least one active agent having a yield stress ofless than 30 Pa and forming a contact angle with the well of less than90°, wherein the suspension of the film forming composition and theparticulates of the at least one active agent flows into a film layer inthe well within 20 seconds and has a viscosity below 600 centipoise; anddrying the film using hot air currents to form the oral soluble filmlayer containing the at least one active agent. The multi-layered mayinclude an insoluble backing layer. The multi-layered film may include asemi-insoluble or slow-dissolving backing layer. The multi-layered filmmay have multiple layers each with a different active agent.

In certain embodiments, the dosage may comprise films from two or moreadjacent wells and have different actives which are packaged to beadministered in tandem or concert.

A single slow dissolving mucoadhesive layer may be first depositedwithin a well followed by a droplet or droplets of drug containingsolution in the center of the mucoadhesive composition. The mucoadhesivecomposition when placed within the buccal mucosa may now have theopportunity to adhere on both sides of the composition. This is unliketypical multi-layer mucoadhesive compositions with one side containing abarrier layer and another side containing a mucoadhesive layer withdrug. Stated another way, in this embodiment, the drug containing layer13 or area has smaller outward dimensions (smaller surface area) thanthe mucoadhesive backing layer. In other embodiments, the drugcontaining layer has larger outward dimensions than the mucoadhesivelayer. Similarly, other multilayer embodiments have an insoluble orslowing dissolving backing layer that has larger outward dimensions thana drug containing layer, or have an insoluble or slowly dissolvingbacking layer with smaller outward dimensions than a drug containinglayer. Drying may occur after all layers are deposited, or after one ormore layers is deposited.

By “slowly dissolving” layer, we mean a layer that dissolves in morethan three minutes, preferably more than five minutes, preferably morethan ten minutes, and most preferably more than fifteen minutes, in itsintended usage site (e.g. buccal, sublingual, interoral, vaginal, anal,wound-care, etc.).

Certain embodiments involve effervescent films. Typically, these aremultilayer; at least one layer comprises the base and at least onedistinct layer comprises the acid. These layers may be separated by abarrier to deter confluence or mixing of the acid and base duringmanufacture. Drying a first layer before depositing the next layer canalso deter and substantially eliminated mixing during manufacture.

In still other embodiments, multiple mucoadhesive layer points (i.e.discrete mucoadhesive areas) are deposited onto a drug containing layer.

In certain embodiments, A multilayer oral soluble film made by deposit,comprising at least one drug containing layer, a separate slowlydissolving backing layer not comprising drug, wherein the drugcontaining mucoadhesive layer has smaller outward dimensions than thebacking layer.

For example, as shown in FIGS. 10A, 10B, a single slow dissolvingmucoadhesive layer 12 may be first deposited within a well followed by adroplet 13 or droplets of drug containing solution in the center of themucoadhesive composition 12. The mucoadhesive composition 12 when placedwithin the buccal mucosa may now have the opportunity to adhere on bothsides of the composition. This is unlike typical multi-layermucoadhesive compositions with one side containing a barrier layer andanother side containing a mucoadhesive layer with drug. Stated anotherway, in this embodiment, the drug containing layer 13 or area hassmaller outward dimensions (smaller surface area) than the mucoadhesivebacking layer 12. In other embodiments, as shown in FIGS. 11A and 11B,the drug containing layer 13 has larger outward dimensions than themucoadhesive layer 12. Similarly, other multilayer embodiments have aninsoluble or slowing dissolving backing layer 12 that has larger outwarddimensions than a drug containing layer 13, or have an insoluble orslowly dissolving backing layer 12 with smaller outward dimensions thana drug containing layer 13. Drying may occur after all layers aredeposited, or after one or more layers is deposited.

Another aspect of the present invention relates to a method of making anoral soluble film, containing at least one active agent. The methodincludes providing a well of a predetermined size; depositing a filmforming composition in the well; depositing an active agent compositionin the well, the active agent composition being different than the filmforming composition, the film forming composition and the active agentcomposition forming an admixture in the well; and drying the admixturein the well.

Depositing of the film forming composition in the well and depositing ofthe active agent composition in the well can be carried out sequentiallyor simultaneously from two (or more) separate deposition devices. Ifsequential deposition is used, the active agent composition ispreferably but not necessarily deposited in the well first and then thefilm forming composition is deposited in the well, or vice versa giventhe characteristics of the materials to be deposited and intendedproducts attributes. Various iterations may be employed of film formingcomposition and active agent compositions.

In another aspect of the invention, a method of making an oral solublefilm, containing at least one active agent, includes providing a well ofa predetermined size; depositing a film forming composition including atleast one active agent in the well, the film forming composition havinga viscosity below 2000 centipoise; and drying the film formingcomposition in the well.

In still another aspect of the invention, a film forming composition,suitable for making an oral soluble film, has sufficiently low viscosityand surface tension to flow into a film without mechanical interventionwhen deposited in a well.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a roll of pre-formed molds or wellsprior to filling.

FIG. 2 is a perspective view showing a deposit device filling a well ofthe roll of pre-formed molds or wells.

FIG. 3 is an enlarged view of a portion in FIG. 2 showing a depositdevice filling a well with a film former composition.

FIG. 4 is an enlarged view of a portion in FIG. 2 showing a depositdevice filling a well with active pharmaceutical ingredient withoptional excipients, in particulate form.

FIG. 5 is a perspective view showing a drying device deploying hot aircurrents from above the roll of film wells (which have been alreadyfilled).

FIG. 6 is a perspective view showing adhesive being applied to welledges of bottom sheet.

FIG. 7 is a perspective view showing a roll of wells, with films (anddrug) deposited, films formed and dried, and guideposts inserted in theends of the roll of wells for alignment of the top sheet which is placedover the bottom sheet.

FIG. 8 is a perspective view showing a roll of wells, with films (anddrug) deposited, films formed and dried, guideposts, and serration ofindividual doses within the roll of wells.

FIG. 9 is a perspective view showing a finished dosage form removed froma roll of wells, the breakage lines occurring at the lines of serration.

FIG. 10A is a top plan view of a first embodiment of a multilayer oralsoluble film made by deposit.

FIG. 10B is a cross-sectional view of first embodiment of a multilayeroral soluble film made by deposit along lines 10B-10B of FIG. 10A.

FIG. 11A is a top plan view of a second embodiment of a multilayer oralsoluble film made by deposit.

FIG. 11B is a cross-sectional view of second embodiment of a multilayeroral soluble film made by deposit along lines 11B-11B of FIG. 11A.

FIG. 12 is a schematic view of a system for manufacturing apharmaceutical active agent-containing oral soluble film by deposit in apattern.

FIG. 13 is a cross-sectional view of a well contained in a sub-well.

FIG. 14 is a schematic view showing a system and method forpre-releasing the film from the bottom of the mold or well.

FIG. 15 is a plan view of a rectangular-shaped well.

FIG. 16 is a cross-sectional view of the rectangular well along lines16-16 of FIG. 15.

FIG. 17 is a cross-sectional view of a well according to certainembodiments of the invention;

FIG. 18 is an enlarged portion of FIG. 17.

FIG. 19 is an enlarged portion of FIG. 17.

FIGS. 20A and 20B are cross-sectional views of a well that is convex andcan be pushed to concave to present the film for easy access by thepatient.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention relates to a system formanufacturing an oral soluble film with an active agent, e.g., apharmaceutical oral soluble film by the deposition of active and filmformer composition separately into a mold or well.

One aspect of the present invention relates to a system formanufacturing an oral soluble film with an active agent, e.g., apharmaceutical oral soluble film by the deposition of activepharmaceutical agent(s) and film former together into a mold or well.

One aspect of the present invention relates to a system of continuousmanufacture (formation of oral soluble films) and primary packaging ofthe oral soluble films.

One aspect of the present invention relates to a system formanufacturing an oral soluble film in which the active agent isdeposited into a mold or well separately from the film former, and thedrug binds or diffuses adequately mixes into the final, dried filmmatrix.

One aspect of present invention relates to a method of forming an oralsoluble film with an active agent, e.g., a pharmaceutical oral solublefilm without direct mechanical intervention to spread and/or coat and/orcast the composition into a film, such as by deposit of a sufficientlyflowable film former composition into a well or mold and.

One aspect of the present invention relates to the use of a compressedgas to encourage and/or speed the flow of a film composition into a filmshape in a mold or well.

One aspect of the present invention relates to the use of a compressedgas to encourage mixing of an active agent with a film formercomposition in a mold or well.

One aspect of the present invention relates to the use of briefvibration to encourage and/or speed up mixing of an active agent with afilm former composition in a mold or well.

One aspect of the present invention relates to the use of briefvibration to encourage and/or speed up the flow of a film compositioninto a film well shape.

One aspect of the present invention relates to the manufacture of afilm-sheet 1 to 40 mils (measured as dry thickness). This isnon-limiting and the methodology here allows for thick films and fordermal products.

One aspect of the present invention relates to a mold or well shape thatis optimized for film formation by deposit method.

One aspect of the present invention replaces to mold or well materialthat is selected to be a suitable surface energy substrate to facilitatewetting and spreading of film former composition, i.e. low contact angleand/or surface tension.

One aspect of the present invention relates to pre-treating a mold orwell with a surface active agent, a surfactant, or other agent to eitherpromote flow of the film composition, and/or promote easier release ofthe dried film.

One aspect of the present invention where the surface of the well mayhave modified textures, indentations, coatings or heat treatment to varyor affect the flow pattern of the film composition.

One aspect of the present invention relates to a composition suitablefor making an oral soluble film where the viscosity and/or surfacetension and/or interfacial tension of the composition (with thewell/mold material, as applicable) is selected to promote flowability ofsaid composition sufficient to form a film in a mold or well, and incertain embodiments to form such a film rapidly in such mold or well.This categorically teaches away from cast film art in that highviscosity is antithetical to successful formation of a deposit byprecluding adequate flowability of the film former composition into amold or well.

One aspect of the present invention relates to a film former compositionwith sufficient wettability to mix adequately in a mold or well with aseparately deposited active.

One aspect of the present invention relates an oral soluble film madewith one or more low molecular weight polymers as film formers

One aspect of the present invention relates to a composition suitablefor making an oral soluble film by the deposit method, where suchcomposition is not capable of being wet cast into a film usingtraditional wet cast coating technologies (e.g. by three roll coater, ordoctor blade).

One aspect of the present invention involves an alignment system toensure the mold or well sheet is aligned with the top sheet. Forexample, aligning openings on the well sheet and the top sheet may beused so that through, for example, a pin type alignment each is properlyoriented to the other.

One aspect of the present invention relates to a drying process that issuitable for the deposited composition to immediately flow into theshape of the mold or well prior to becoming too viscous to flow as aresult of loss of solvent effecting viscosity increase.

One aspect of the present invention relates to the material of the moldor well selected that is suitable for the flow of the composition into afilm.

One aspect of the present invention relates to the material of the moldor well selected to simultaneously allow the flow of the readily flowingcomposition while also allowing the dried material to be readily removedor peeled away from the well.

One aspect of the present invention relates to the design of the mold orwell so that a user can readily remove the film.

One aspect of the present invention can allow the dosage unit to besealed (primary packaging) on the same production line as the film ismanufactured if desired. Alternatively, the dosage unit can be sealed onan adjacent packaging line. Standard packaging at a later time is alsoallowable.

One aspect of the invention deals with the stop-start (or stutter) ofthe film-by-depost production line, which may be in connection, interalia, with deposit of a material, drying of the material or drying of alayer, or application of the topsheet.

One aspect of the invention relates to the substrate/laminate layer withpre-formed wells made at line or before line by blister forming methods.

One aspect of the present invention relates to the blisters beingcollapsible such that when the substrate layer is rolled up on itself,the film within it is loosened enabling easy subsequent removal by theuser.

One aspect of the present invention relates to the manufacture andpackaging of an oral soluble film, including a multi-layer film, withminimal composition and API loss (less than 30% preferably less than20%, more preferably less than 10%, even more preferably less than 5%).

One aspect of the present invention relates to a oral soluble filmcomposition that has little or no yield stress. Such compositions areparticularly well suited for the present invention (i.e. formation of anoral soluble film by deposit method).

One aspect of the invention involves a rolled adhesive onto the driedbottom sheet/mold/well edges, but excluding the interior of thesheet/mold/wells, so that top sheet can be adhered.

One aspect of the present invention relates to a topsheet on the filmwells that is printed for the blister, i.e. not gangprinted.

One aspect of the present invention relates to indicia or identifiers onthe individual film that are not gangprinted.

One aspect of the present invention relates to a film former compositionwith a viscosity below 2000 centipoise, preferably below 1000, morepreferably below 600 centipoise, still more preferably below 300centipoise. Such measurements, in the case of a Non-Newtonian filmformer composition, are measured at low shear rate, <10 s⁻¹

One aspect of the present invention relates to the use of viscosityreducing agents in oral soluble film compositions. This teaches againstthe viscosity needed in traditional, wet cast films.

One aspect of the present invention relates to an oral soluble film withsufficiently uniform thickness and appearance for the user, withoptional uniform distribution of components in the film. One embodimentof the present invention relates to an oral soluble film that does nothave uniform distribution of active agent within the film.

One aspect of the present invention relates to an oral soluble film,made by deposit method, with <20% variability in height, preferably with<10% variability in height (measured from the thickest portion of thefilm to the thinnest portion, measured vertically). Other embodiments ofthe oral soluble film of the present invention will have greatervariability, particularly where unique shapes are intended with variedfilm topography

One aspect of the present invention relates to an oral soluble film,made by deposit method, with one or more active agents, e.g., activepharmaceutical agents, wherein the content of said active pharmaceuticalagent(s) varies less than 10% from the label claim, preferably less than5%, preferably less than 2% from the label claim.

One aspect of the present invention relates to a multi-layer film madeby deposit method.

One aspect of the present invention relates to the manufacture of atransdermal film, in whole or in part, by the deposit method.

One aspect of the present invention relates to the manufacture of filmsby deposit for wound care, internal or external to the body.

One aspect of the present invention relates to the manufacture of filmsby deposit for use in the nasal cavity.

One aspect of the present invention relates to the manufacture of filmsby deposit for use in the vagina.

One aspect of the present invention elates to the manufacture of filmsby deposit for use in the anal cavity.

One aspect of this invention is for film comprising a surface numbingagent for use in the skin and in the mouth and in the anus.

While the primary embodiment involves a soluble film for oral use,non-oral uses are expressly contemplated in connection with films of thepresent invention made by deposit.

The composition may be deposited within the well as a single or multipledroplets or sprays at a single centered or off-centered position withinthe well. Or as multiple discrete droplets or sprays at multiple laterallocations within the well for differential deposition. This may beaccomplished by multiple nozzles or, as shown in FIG. 12 by a singlenozzle 3 located on a movable X-Y gantry 14 that can move in a lateral(or other) motion to lay droplets or strands of solution (or powder)into the well 2 in various patterns. One or more nozzles may be on amovable x-y gantry that deposits into the well in depositing pattern, aparticular geometric shape, or both. The geometric shape may bepolygonal, circular, elliptical, zig zag or any other shape caused whenthe nozzle is not stationary. The shape may involve articulation of thenozzle, movement of the well during deposit or both.

In another aspect of the invention, a method of making an oral solublefilm, containing at least one active agent, includes providing a well ofa predetermined size and/or shape; depositing a film forming compositionincluding at least one active agent in the well, the film formingcomposition spread within the well by using mechanical means to move thedepositing nozzle around to deposit at different locations within thesame well to ‘paint’ different areas of the well with film formingcomposition in patterns to obtain film with variable thickness orridges. For example, as shown in FIG. 12, the nozzle 3 can articulate ina swinging fashion as shown by the arrows 15. In this manner, the filmformer solution can be deposited in a shape selected from the group of:circular, elliptical, polygonal or zig-zag. The nozzle can pulsateon-off during deposit or may be configured to deposit with continuousflow.

One aspect of the oral soluble film where the edge or rim orcircumference or border of the film is thicker than the center of thefilm to improve tear resistance of the film. This may be accomplished bydifferential deposition or by modifying the geometry of the wellstructure. For example, the well structure may have a deeper perimeterat the edge or rim to effect increased thickness at the edge or rim ofthe film.

In certain embodiments, the edge (or the edge in a particular geographyof the film, i.e. not the entire perimeter, edge, rim, circumference)has a thickness that is more than 10% thicker than the center,preferably more than 20% thicker than the center, even more preferablymore than 30% thicker than the center. For example and withoutlimitation, at least part of the edge only may have increased thicknessover the center.

In certain embodiments, the edge (or the rim, perimeter, rim orcircumference) (or the edge in a particular geography of the film, i.e.not the entire perimeter (or rim, or circumference)) has a thicknessthat is more than 10% thicker than the center of the film or than thefilm's average thickness, preferably more than 20% thicker than thefilm's average thickness, even more preferably more than 30% thickerthan the film's average thickness. For example, and without limitation,at least part of the edge may have increased thickness over the center.This can be achieved using a well of the type shown in FIGS. 17 and 19,described hereinafter.

One aspect of the invention where the well structures may be modified byusing 3-D printed or CNC milled inserts placed within a larger mold toachieve a variety of quickly changeable mold shapes for different shapesand size of film.

One aspect of the invention is to allow for intermittent movement of thewell substrate along the production line as opposed to the continuousmovement demanded by the wet casting method.

Preferred embodiments of the present invention is described herein withreference to FIGS. 1-9, which schematically show examples of the methodand system of the present invention. However, applicants' invention isnot limited to the particular embodiments/examples shown in the figures.

FIG. 1 shows a roll 1 of pre-formed molds or wells 2 prior to filling bydeposit. In other embodiments, the mold or well 2 may be formed on theproduction line itself from flat roll stock.

FIG. 2 shows a deposit device 3, described in more detail hereinafter,filling a well. The deposit device 3 may be depositing film formercomposition, an active agent composition with optional excipients, or afilm former composition complete with an active agent within it. In FIG.2, the film former composition, the active agent composition withoptional excipients, or a film former composition complete with anactive agent are all designated generally with the reference numeral 4.

FIG. 3 shows a deposit device 3 filling a well 2 with a film formercomposition 4 a.

FIG. 4 shows a deposit device 3 filling a well 2 with a composition 4 bincluding active ingredient(s) with optional excipients, in particulateform.

In one aspect of the present invention, a film forming composition 4 ais deposited in each well 2 and an active agent composition 4 b isdeposited in each well 2, the active agent composition 4 b beingdifferent than the film forming composition 4 a. The film formingcomposition 4 a and the active agent composition 4 b form an admixturein the well 2. The film forming composition 4 a and the active agentcomposition 4 b may be separately deposited in the well 2 at the sametime, e.g., through two separate deposit devices 3. Alternatively,depositing of the film forming composition 4 a and the active agentcomposition 4 b in each well 2 are carried out sequentially; in thisembodiment, it is preferable but not necessary that the active agentcomposition 4 a is first deposited in the well and then the film formingcomposition 4 b is deposited in the well.

FIG. 5 shows a drying device 5 deploying hot air currents from above theroll of film wells 2 (which have been already filled). In certainembodiments, drying occurs in a drying tunnel (here the tunnel is cutaway for better visibility).

FIG. 6 shows adhesive 6 being applied to well edges, i.e., to areas ofthe bottom sheet 1 outside the wells 2 by an applicator 7.

FIG. 7 shows a roll 1 of wells 2, with films (and drug) 4 deposited,films formed and dried, and guideposts 8 inserted in the ends of theroll 1 of wells 2 for alignment of a top sheet 9 which is placed overthe bottom sheet 1.

FIG. 8 shows a roll 1 of wells 2, with films (and drug) 4 deposited,films formed and dried, guideposts 8, and serration 11 of individualdoses 10 within the roll of wells. Serration can occur in the roll stockprior to deposit of film composition 4 or after the manufacture of film4.

FIG. 9 shows a finished dosage form 10 removed from a roll 1 of wells 2,the breakage lines occurring at the lines of serration 11.

A summary comparison of films made by certain embodiments of the depositmethod of the present invention and films made by wet casting isprovided below.

Parameter/Attribute Wet Cast Oral Soluble Film Deposit Oral Soluble FilmViscosity of film former High Low or optionally high compositionFlowability of film former Low/None Low or optionally high compositionWhere Active Drug is Mixed with film former Deposited separately fromadded in process prior to coating on substrate film former composition(or optionally together) Substrate in Continuous Coating must occur onDeposit in mold/well is not Motion substrate in continuous continuous(optionally motion continuous) Coating substrate removal Coatingsubstrate must be Substrate is typically not removed in conversion priorremoved; deposited in final to packaging primary packaging Angle of Flowof film High angle of flow of film Low angle of flow of film formercomposition former composition former composition Stoke's Law employedto Stoke's Law employed to Stoke's Law has virtually maintain drugcontent maintain drug content no application where drug is uniformity infilm former uniformity in film former deposited separately. compositioncomposition Controlled drying necessary Controlled drying necessaryControlled drying not for drug content uniformity for drug contentuniformity necessary for drug content uniformity Cutting of filmspecific size Cutting of film specific size Cutting of film not requiredrequired to make final required to make final to make final dosage formdosage form dosage form Rapid drying required for Rapid drying requiredfor Rapid drying not required drug content uniformity? drug contentuniformity for drug content uniformity Active Drug Waste (loss in HighAPI Waste Low API Waste process) Coating steps for Bi-layer Typicallytwo separate steps Can be made in single film of coating deposit step.Cost for Bi-layer Typically expensive (two Marginally longer depositsteps) step. Inexpensive Low Dose Content Potentially challenging Notchallenging Uniformity Air bubbles, voids and Air bubbles, voids and Airbubbles, voids and surface defects create surface defects create surfacedefects do not create content uniformity issues content uniformityissues content uniformity issues Separation of incompatible DifficultSimple using separate drug actives in a deposit steps combinationproduct Film Thickness Film thickness must be Film thickness can vary asuniform for drug content long as volumetrically uniformity accuratedroplet is deposited Liquid suspension, solution, Can be depositedefficiently Deposition is not difficult. emulsion, gel, jellies, jams,but cannot be cast mousse, pudding, gelatin, etc.

One aspect of the present invention is to enable film formulations whichwould have not have adequate mechanical properties for traditional oralsoluble film manufacturing, i.e. ability to wind into a roll, ability tobe trimmed and covered, ability to be released or peeled away fromsubstrate, and ability to be converted in a conventional film packagingmachine (e.g. a Doyen Medipharm machine). For example, a formulationthat has insufficient tensile strength for conventional conversion, or aformulation that has propensity for elongation under stress, would beunable to be converted using conventional means but is able to bemanufactured using the deposit method.

The drug that is being deposited may be in the form of a powder or asolution in which case the drug solution in the bulk tank from which itis being deposited into wells in aliquots does not have to be stirred.However, it may also be a suspension of fine drug particles that may becontinuously and vigorously stirred while the suspension is beingdeposited in aliquots into wells. Continuous stirring is generally notpossible with viscous drug suspensions such as those used informulations for continuous coating due to the induction of air into themix which causes film defects and precludes collection of good anduniform product. In the deposit method, the low viscosity generally doesnot allow air bubbles to form in the film as they are immediatelydissipated as the deposited liquid flows into the well as a thin layer.Embodiments where the active drug suspension is separately depositedinto the well or mold, it may need to contain none to very lowquantities of binder allowing incessant and high-speed mixing therebypreventing settling and ensuring uniformity.

Applicants teach against the fundamental theme of prior film art (Yanget al, Horstman, etc), namely, the use of high viscosity to (i) preventmigration of the active and preserve uniformity of dose content in themixing stage, (ii) enable the required coating thickness of the filmcomposition, and (iii) prevent migration of the active and preservecontent uniformity in the drying stage. Instead, high viscosity (andsurface tension) here work contrary to (i) the ability to deposit thefilm former composition into the well or mold, and (ii) the ability ofthe film former to flow (and reasonably rapidly and without mechanicalintervention) into a film within the well or mold.

Deposit of a high viscosity film former composition such as those taughtby Yang et al. in a well or mold will not generally result in a film atall, but rather simply a dollop-type shape of film former absentphysical, mechanical intervention to spread the film former into a film(like a doctor blade, or other coating apparatus). Viscosity and surfacetension simply prevent such compositions from flow, let alone sufficientflow to form a film.

It is important to note that to accurately dose and spread film formerin a well, a relatively low viscosity is required (and surface tension),otherwise the material will refuse to spread in the well and simple forma dollop of material in part of the well.

Moreover, the embodiments where the drug active is separately depositedin the well or mold, high viscosity and lack of wetting can actuallyinterfere with mixing of the drug active into the film matrix, therebypreventing adequate mixing of drug and film former composition fromoccurring.

High viscosity is also not needed to enable coating thickness of thecomposition; in the deposit method of the present invention the filmcomposition can be readily deposited as high as the sides of the well ormold. In certain embodiments, surface tension allows the composition tobe deposited higher than the sides of the well or mold, and then shrinkbelow during drying which may form slightly cup shaped films from a sideprofile.

Film former and active are metered into the wells either singly or bymultiple metering devices.

It is important to note that to accurately dose and spread film formerin a well, a relatively low viscosity is required (and surface tension),otherwise the material will refuse to wet and spread in the well andsimply form a dollop of material in part of the well. Various methods topromote spread are discussed herein.

Preferably, the after deposit, the film former composition will flowinto a film in a well or mold within ninety seconds, preferably withinsixty seconds, more preferably within twenty seconds, even morepreferably within five seconds, and most preferably within one second.By flow into a film, Applicants mean that the film former compositionwill either reach the ends of the mold/well, or otherwise cease to flow.

This time is important as it will impact production line speed. Outputof course may be improved by using a bank of feeders (filling multiplewells forward and horizontally at one time).

Both viscosity and surface tension are connected theoretically tointer-molecular forces, but they are still very different concepts.

Shear Stress is a force that acts on a fluid to cause flow and theviscosity determines velocity gradient. Viscosity is an intrinsicproperty of the fluid itself. Viscosity is the ratio of the shear stresstensor to the rate of deformation tensor. Roughly speaking, viscositydetermines how momentum is transported through a fluid during flow, asit is a measure of resistance to flow.

Contact angle acts not inside the substance, but only on its interfacialboundary with substance of another phase, even if nothing moves. It isnot a property of the substance itself, but of a pair of these phasesmeeting at the boundary. Often the expression “contact angle of water”is used; but what is meant is contact angle of the pair water-air.Combinations water-glass or water-oil have different value of contactangle. Roughly speaking, contact angle says how much energy ofinteraction is stored when two chemical species are in mutual contact,even in equilibrium.

One way to think about the effective flowability of a film formercomposition for a given type of surface, is Young's equation. A drop ofliquid when placed on a flat, homogenous solid surface comes toequilibrium, assuming a shape which minimizes the total free energy ofthe system. The angle between the liquid and the solid is called thecontact angle, the angle being measured through the liquid. The contactangle may be calculated if the surface tension and interfacial tensionare known, using Young's equation (seeen.wikipedia.org/wiki/Wetting#Ideal solid surfaces, which isincorporated by reference as if fully stated herein, as retrieved on3/26/17). For certain embodiments of the present invention, surfacetension and interfacial tension are minimized to reduce the contactangle of the system.

To wet the substrate well, the contact angle must be <90°.

One way to think about the rate of flow or spreading of the composition,is Tanner's law. Tanner's law teaches that the rate of spreading of adroplet is related inversely to the viscosity of the droplet. See Bonnet al, “Wetting and Spreading” (hereby incorporated by reference as iffull set forth herein, and Krishnakumar, “Wetting and SpreadingPhenomena, available here:guava.physics.uiuc.edu/˜nigel/courses/563/Essays_2010/PDF/Krishnakumar.pdfand similarly hereby incorporated by reference as if fully set forthherein).

The preceding teaches away from Yang et al, wherein the film compositionyields a high contact angle on the substrate, which allows forrelatively thick non-flowing compositions. In fact, wet cast filmcoatings are so thick and unflowable, Watson has taken the position inits Suboxone ANDA litigation that its film coating should be understoodto be a solid immediately after coating: “The physical evidencedemonstrates that Watson's casting dispersion forms a viscolelasticsolid when the forces of mixing and pumping cease, which happens beforethe initiation of drying . . . . The inspection video demonstrates that:(1) by the time Watson's casting dispersion travels up a steep inclinefor 30 seconds, and prior to any drying, it has already gainedsufficient structure to “lock-in” and prevent migration of the activesuch that the casting dispersion does not flow backwards down theincline, as it would if it were a viscoelastic liquid; (2) Watson'sfilms are cast as in discrete lanes at the width of the final film,which would not be possible if the casting dispersion were aviscoelastic liquid . . . ” From Document 186, pp. 10-11, Case1:14-cv-01574-RGA (District Court for Delaware). Thus Watson is statingto the Court that its film composition is simply not flowable at all,absent the mechanical intervention of the coating apparatus

Film compositions of the present invention may be non-Newtonian orNewtonian. It should be noted that in the preferred embodiment, nomechanical force is applied to the film composition after deposit intothe mold or well to encourage spreading/flowing of the film formercomposition. Accordingly, shear thinning or pseudo plastic attributes donot materially effect flowability in the well or mold since there isgenerally no mechanical source of shear stress other than gravity toaffect a reduction in viscosity (as we would see in a coatingapparatus).

It is contemplated in certain embodiments that shear force may beachieved by pressurized delivery of film former composition into thewell (such shear being affected by the impact of the film formercomposition against the well). However, there are practical limitationson how much shear can be achieved in this manner with substantialabsence of splatter outside of the well. Nozzle design can be optimizedto reduce or mitigate splatter. Nozzles may also have check valves andother features to prevent dripping of solutions from the nozzle orprevent strands of solution from the nozzle to the well.

Film compositions of the present invention may have little or no yieldstress. In certain embodiments, film compositions of the presentinvention will have insufficient yield stress to prevent flow on anincline greater than 45%, greater than 25% or even greater than 10%. Incertain embodiments, the film composition of the present invention willhave a yield stress <50 pa, preferably <30 pa, most preferably <15 pa.

The focus of the present invention teaches away from the thinking in thecast film art to use high yield stress to prevent sedimentation of drugparticles and other components.

Continuous or Stuttered Manufacture

Embodiments of the present invention may employ continuous manufactureor stuttered (intermittent) manufacture.

In conventional wet casting, the substrate must be coated continuously.There is time (and waste) associated with bringing the coating processonline to operating parameters with appropriate coating thickness. As apractical matter, the process must be continuous. This continuouscoating typically implies long drying ovens.

Certain embodiments of the deposit method allow for a stutteredmanufacturing process. One or more molds/wells is filled. At this time,the mold/well rollstock is stationary or moving (relative to the fillerapparatus). After filling, the mold/well can be moved to a dryer. Incertain embodiments, the filler may move with the mold/well so as tohave no relative speed as between them during filling. Again, the moldsor wells may continuously move through the dryer or it may be stationaryin the dryer. The dryer apparatus may also be deployed after filling ina single place (i.e. without the mold/well moving).

In many embodiments, the deposit of film former composition and drug(and ensuing flowing into a wet film in the mold/well) is faster thanthe drying stage. Because deposit is non-continuous, in someembodiments, the mold/wells may be in stage blocks that can be placed ormoved on belt feeds into an oven on multiple levels. This allows for asmall dryer footprint to accommodate relatively high production.

In other embodiments, there may be two separate banks of feeders, sayfor multi-layer films. One bank of feeders is placed before an initialdrying section. A film is formed (for example, a backing layer). Afterinitial drying, a second feeder bank deposits the next layer (forexample, a drug containing layer). After this second feeder bank, thereis another drying stage. The line may stutter, at the same time, orseparately stutter.

The stuttered option for deposit allows for a very efficientmanufacturing in terms of footprint. Skilled artisans will appreciatethe various configurations for deposit, drying, and packaging overlay onthe molds/wells. A circular or other return layout between filler anddryer may be employed where a follow deposit is desired to be made to aninitial dried film layer.

A key advantage is the manufacture of the film product, from start tofinished primary packaging, in a single line.

Methods of Deposit

Generally, the materials will be deposited in the well or mold using aflowmeter enabled feeder (any suitable flowmeter and feeder may beemployed). The flowmeter may measure mass and/or volumetric flow rate ofa liquid or solid. K-tron is a non-limitative example of a suitablefeeder. Any suitable apparatus that can reliability deposit filmerformer composition or drug may be employed.

Apart from gravity feed, pumps may be employed to feed the material intothe well. Speed of deposit is important for line speed/product output.Moreover, it may be desirable to inject material into the mold or wellwith some additional force beyond gravitational force.

A bank of feeders may be employed to allow for a number of wells/moldsacross (and forwards) to be simultaneously. Optionally, the bank offeeders may source from a single mother tank, or from a plurality oftanks (or hoppers).

Where the drug is deposited separately, multiple feeders may beemployed: one to supply an active drug (or drug combination) (optionallywith one or more suitable excipients), and one to supply the film formercomposition. The drug may be contained in a single mother tank (orhopper), or a plurality of tanks (or hoppers).

If the active drug is a particle, the active drug may be delivered indry powder form, or in solution (where soluble), suspension or emulsion.One advantage of dry powder form is to avoid the time during which thedrug active is in contact with liquid (which can avoid problems withcrystallization, drug stability, and the degradation of taste masking orcontrolled release systems).

Where the drug is soluble, certain embodiments may use a pH for the drugsolution optimized for solubility (where pH buffer of the film formercomposition uses a different, stronger buffer to control the ultimate pHof the dosage form). The drug may be solubilized in any appropriatepolar or non-polar solvent.

One advantage of a solution, suspension or emulsion, is to promotemixing of the pharmaceutically active agent with the film formercomposition, though it is demonstrated in examples below that dryparticles can be adequately mixed with separately metered film formercompositions.

The feeders may employ nozzles that are optimized to promote mixing. Forexample, the nozzle may be selected to broadly disperse material in thewell. The nozzle may be aimed to initiate flow in the well or mold.Where the drug is administered separately, the nozzle depositing thedrug and the nozzle depositing the film former composition may be aimedin a complimentary fashion to promote mixing of the two. As anon-limitative example, the nozzles may direct the flow of the filmformer composition and drug in opposite directions. Nozzles may have adesign to encourage mixing. In addition, nozzles may be used that have aspray pattern which is matched or otherwise calibrated to the welldimension.

Nozzles can be articulated to move position relative to the geography ofthe well or mold during deposit. Such articulation may be useful for arange of purposes, including without limitation: (a) more evenlyspreading the polymer and/or drug in the well or mold; (b) permittingfaster deposit of the material to shorten the time it takes to spreadthe material adequately in the mold or well; and (c) with a lessflowable composition, to create an intentional (intended) thickness incertain geographies of the film.

Nozzle articulation, when depositing, may be circular, square,trapezoidal, or any shape. It may deposit in parallel lines, or inzig-zag fashion. The nozzle may disperse continuously duringarticulation (continuous flow), or may pulsate on-off, in some casescoordinated with the movement-geography of the nozzle articulation.

Pressure from the nozzle may be constant or may pulsate intentionally.

The above described nozzle articulation is in addition to embodimentswhere the feeder bank may itself move in a coordinated fashion with thewells or molds to be filled.

Where the drug is administered separately from the film formercomposition, the two may be deposited in sequence, or contemporaneously(in which case the deposit rates may be calibrated in terms of time), ormetered in a rotating sequence (for example and without limitation, filmformer composition, drug: drug, film former composition). Where multipledrugs, and/or multiple film layers are used, the sequences can becomemore coupled (for example, and without limitation): Drug, film formercomposition, drug, film former composition. Film former composition,drug, film former composition, drug, film former composition. Backinglayer composition, drug, film former composition. Backing layercomposition, film former composition, drug. Drug, film formercomposition, backing layer composition. Film former composition, drug,backing layer composition.

Where delivered separately, each of the film former composition and thedrug (be it in particulate, solution, suspension, emulsion etc) mayoptionally be paired with any suitable excipient.

Separate administration of film former composition from drug is thepreferred embodiment. First, the viscosities of a film formercomposition to resist sedimentation of the active would be too high forthe film-by-deposit method of the present invention. Second, evensoluble drugs may tend to come out of solubility in the film formercomposition, due to the relative low levels of solvent, interaction withother materials in the film former composition, and other chemicalprocesses. Generally, greater control and reliability of target dosedeposit is associated with separate administration of drug.

Drugs may be separately and sequentially deposited in the case ofincompatible drugs. For example, multiple layers may deposited, eachwith a different active. In certain embodiments, the second layer isdeposited after the preceding lawyer has been dried. In some instances,the active and the film former and the excipients could all be in onemix and dispensed simultaneously through a single deposition from onedeposer. In embodiments in which the second layer deposited after thefirst layer is dried, it could be on top and include, withoutlimitation, active in sustained release form, taste masking, absorptionenhancers, pH modifiers and other modifiers such as an acid and base toproduce effervescence. When introduced however, with things likecoloring the mix, the top could become the bottom re the patientdirections.

It may be desirable to heat the film former composition to promoteflowability prior to, or after deposited in the mold or well. Attentionmust be paid to degradation temperature, and the sustained temperatureshould not exceed the drugs's known degradation temperature. Temperatureincrease will tend to decrease viscosity and surface tension providedthat the solvent is not permitted to escape (or otherwise notreplenished).

The Well or Mold

In this application, we use the terms well and mold interchangeably.

The well or mold will generally be of suitable depth to contain the wetheight of the desired film composition. As a practical matter, the filmtends to reduce in thickness when dried.

The well or mold may be pretreated with silicone, hydrophobic agents,surfactants or and other suitable material that promotes flow of thefilm composition and/or promotes release of the final dry film from thewell or mold. In certain embodiments, the pre-treatment agent to promoterelease is a powder. Preferably, the powder is not soluble (orsubstantially insoluble) in water or other solvent deposited with thefilm forming composition. In certain embodiments, the pretreatment agentis combined with a sweetener and/or flavor so as to avoid impartingunpleasant taste to film dosage unit.

The pretreatment agent may be applied to the forming material before orafter the formation of the well or mold. However, in preferredembodiments it is applied after formation of the well or mold, andpreferably via a spray method. Individual spray pump nozzles may beemployed, particularly to avoid or substantially avoid application ofthe pre-treatment agent to the outer portion of the well or mold wherethe top sheet is sealed.

Round shapes of the well or mold are desirable, but non limiting, toform a round film. Circular shapes may be particularly desirable butsquare or rectangular forms are also possible, as shown in FIGS. 15 and16. In the case of circular shapes, the film composition can bedeposited in the center and flow outward. Any regular or irregularpolygonal shape may also be possible. The mold or well may also beshaped for form three dimensional attributes on the bottom of the film.

The sides of the well or mold may be perpendicular or angled (outwardfrom the planar bottom surface) as shown in FIGS. 15 and 16. The sidesmay be curved, and the bottom may be curved.

In certain embodiments, the well or mold is sufficiently flexible toallow a consumer to readily push the bottom of the well or mold up topresent the film for easy access by the patient. In one embodiment shownin FIGS. 20A and 20B, the well 2 is convex (see FIG. 20A) but can bepushed to concave (see FIG. 20B) to present the film 4 for easy accessby the patient. In certain embodiments, when pushed to concave, the wellstays concave. In other embodiments, the well snaps back to convex whensupport is removed.

In other embodiments, the sides of the well are designed to collapseupwards towards the top sheet (typically after the top sheet has beenremoved prior to use) to present to film for easier access. For example,as shown in FIGS. 17 and 18, the sides of the well 2 may be formed likeor in an accordion shape 18 as more clearly shown in FIG. 18. Accordionfolds 18 may be angles (i.e. straight line folds, or curves, wavy etc.).The well may collapse upwards will occur when the bottom is pushed up,and the well may be turned “inside out”. In other embodiments, the wellsides may be formed with an intended weak point or weak points tofacilitate the collapse upwards of the well (or again, its turninginside out).

As shown in FIG. 17 and the enlarged view in FIG. 19, the well 2 canhave a portion 19 at the edge (or the rim, perimeter, rim orcircumference) (or the edge in a particular geography of the well, i.e.not the entire perimeter (or rim, or circumference)) shaped to provide afilm formed therein with a thickness that is more than 10% thicker thanthe center of the film or than the film's average thickness as describedearlier.

The well or mold material must be able to withstand drying temperaturesof the drying process, without substantially deviating from its intendedshape.

In certain embodiments, the mold or well is formed using mechanicaltools (including without limitation, dies or stamps) as part of thecontinuous production process. For example, the process may begin with asuitable, flexible rollstock in which the required wells are formed by adie tooling, such formation occurring prior to the deposit step inproduction.

The well or mold may be thermoformed, cold-formed, thermo-cold-formed,or formed using any other known process. Where the well or mold isthermoformed or otherwise heated in connection with in-line formation,it may be desirable to chill or cool the well or mold prior to the filmdeposit stage.

The well or mold may take various forms and shapes, typically configuredto receive a single dose. However, in certain embodiments, the well ormold may accommodate a plurality of doses.

The outer rim of the well or mold may rise at a gentle (acute) anglefrom the bottom of the well or mold (the “side angle”). The use of agentle (acute) angle may permit the use of substrate materials for whichmore severe angles (for example, right angles or tending towards 90degrees) overly stress the substrate material. For example, as shown inFIG. 19, the side angle α of the well is preferably acute, morepreferably less than 60 degrees, still more preferably less than 45degrees, most preferably less than 30 degrees. Comparable curves may beemployed.

The use of gentle side angles may permit more ready use of substratematerials to form the well that are more prone to stress fracture whenformed into severe angles. For example, metal or substantially metalfoils, such as aluminum may have this issue.

In certain embodiments, the well or mold is sufficiently flexible andshallow enough to allow for the well or mold, after deposit, drying, andapplication of top sheet, to be rolled onto itself after drying. Inother embodiments, the wells or molds or cut in blocks and stacked afterapplication of the top sheet.

In most embodiments, the area of the mold or well defines the dimensionsof the film. The mold or well is of fixed size. Generally, the mold orwell with have a deposit surface of 2 square inches or less, preferably1.5 square inches or less. Larger size are possible but smaller sizesare preferred for comfort (in oral use), as well as to speed flow of thefilm composition to ultimate dimensions (i.e. a shorter distance totravel).

In certain embodiments, the molds or wells are fixed and the dried filmsare removed from said molds or wells which can then be reused.

In some embodiments, the well may have an annular shape such that thefilm forming composition is not deposited in the center of the well butaround the center to create a dried film shape with a hole or multipleholes. In one embodiment, the film is in the shape of a circle with ahole in the center, akin to a doughnut.

In certain embodiments, the well or mold is made of metal foil, e.g.,aluminum foil, or plastics, and combinations. Suitable materials mayinclude, without limitation, polyvinyl chloride (PVC), polyethylene(PE), polypropylene (PP), polyester (PET), polystyrene, MYLAR-PET,Copolyesters, Polyvinylidene chloride (PVDC), Polychlorotrifluoroethylene (PCTFE), cyclic olefin copolymers (COC) or polymers (COP),monomer polyethylene (LDPE or HDPE), Ethylene vinyl alcohol (EVOH),Aclar, paper aluminum combinations, paper/PET/aluminum laminates, andother aluminum based laminates.

It some embodiments, a substrate may be inserted (an insert) into thebottom of the well, after well formation and prior to deposit of thefilm materials. Generally, the insert is hydrophobic. The insert howevermay not necessarily be uniform in properties; for example the insert maybe hydrophobic in certain geographies, have non-uniform surface andother attributes intended to help shape the film, and otherwise releasethe film. The insert may be free-floating or adhered to the surface ofthe well.

Heating the Well in Connection with Drying

The use of the well or mold is applies in this case with novelty insofaras the well is used (in most embodiments) in film formation (when filmis deposited on the well as a substrate), film drying and final primarypackaging.

As a result, in most embodiments, the well material used must be capableof withstanding heat exposure associated with the drying methodselected.

Softening of the well material (or components of the well material inthe case of laminate or other multi-layer material) may be experiencedwhere the well material approaches (meets or exceeds) its softeningpoint or melting point.

Softening of the well material may be addressed by having the well 2contained in a rigid sub-well 16 on the conveyor as shown, e.g., in FIG.13, in a shape substantially mated or otherwise adapted to the well 2.The sub-well 16 will typically be larger than the well 2, in order toaccommodate the well 2. In certain embodiments, the sub-well shapemirrors the shape of the well so that the well 2 can be supported whenand if the well softens due to temperature.

The sub-well provides support for a well or mold that is softening fromheat. The sub-well on the conveyor may be chilled or otherwisetemperature controlled, either prior to entering the drier or whilemoving through the dryer. Softening is generally acceptable providedthat substantially no (or no) leaching occurs, or no leaching of anunacceptable impurity occurs, and provided the final well shape is asintended.

In certain embodiments, the sub-well is chilled, prior to deposit, to 15C or below, to 12.5 C or below, or to 10 C or below. In certainembodiments, the sub-well is chilled to maintain a temperature of atleast 10 C below the temperature of air currents in the oven, at least20 C below the temperature of air currents in the oven, at least 30 Cbelow the temperature of air currents in the oven, or at least 4 0 Cbelow the temperature of air currents in the oven.

The sub-well may also be heated. In some embodiments, the sub-wellcomprises a heating element. On other embodiments, the sub-well isheated, including without limitation by hot air currents, prior todeposit of the film solution, or after deposit and prior to entering thedrier.

The Drying Process Typically, the film is dried in the well or mold.Drying can occur with little consideration to migration of drug, unliketraditional film wet casting. One consideration relates to enablingsuitable mixing of the drug (in embodiments where the drug is separatelyadministered from the film forming composition) into the film matrix.

Some consideration may be directed to ultimate release properties of thefilm.

Consideration is given to speed, energy use and efficiency of drying,sufficient evacuation of solvent, and minimizing visible imperfectionson the film.

Another important distinction, is drying time. In conventional wetcasting, the aim is to rapidly dry the film to prevent migration of theactive. For example, US '277 claim 1 describes “rapidly increasing theviscosity of said polymer matrix upon initiation of drying within aboutthe first 4 minutes to maintain said uniform distribution of saidpharmaceutical active by locking-in or substantially preventingmigration of said pharmaceutical active.”

Because the present invention meters the desired drug loading, there isno concern for agglomeration of drug from a content uniformityperspective. This allows for longer drying times. Such longer dryingtimes can serve a variety of purposes, and can be particularly useful inconnection thicker films or for actives that are particularly heatsensitive.

For certain actives, it may be desirable to allow the film to dry atambient conditions, or even controlled, chilled conditions. This may beparticularly desirable for heat-labile materials or other heat-sensitiveactive materials such as biologics including antibodies, antigens,vaccines, proteins, peptides and enzymes.

The solvent or solvents may be partially, substantially or entirelylyophilized.

At the same time, more rapid drying times can be effected as comparedwith traditional casting, without concern for disruptions to the top ofthe film surface.

Since cast film requires viscosity rapidly for uniformity of dosage,specific drying is described, oriented towards early bottom drying toprevent volatile release of solvent and disruption of uniformity. On theother hand, the system herein described does not have that requirementand hence simplified top drying, not limited to air, infrared etc. isvery workable.

High levels of convection (i.e. airflow) may be desired to maximizeheating while the actual air temperature is below the meltingtemperature of the well material (or well material components).Temperature ranges may be selected to balance sensitivity of the activecomponent with requirements for rapid throughput. For typicalpharmaceutical chemicals a drying range from 50 C to 225 C is preferred,with a range from 75-175 C more preferred and a range from 100-150 Cmost preferred. For biological active ingredients, temperatures from30-100 C are preferred with a temperature range from 40-80 morepreferred and a range from 50-70 most preferred

In certain embodiments, the air temperature in the oven is at least 40%below the melting temperature of the well material, preferably at least25% below the melting temperature of the well material, or morepreferably at least 10% below the melting temperature of the wellmaterial. The air temperature may be 40%-15% below the meltingtemperature of the well material, preferably 40%-30% below the meltingtemperature or the well material, most preferably 25% to 15% below themelting temperature of the well material.

In other embodiments, the melting temperature of the well material maybe exceeded, principally for short durations. In other embodiments, theair temperature may be between the softening point and melting point ofthe well material.

Convection speeds, and the direction of air flow must be selected so asnot to disrupt the film's positioning in the well (bluntly, the air flowcannot literally blow deposited solution or the film out of the well orwells). In certain embodiments, air flow is 20 m/s or greater, 30 m/s orgreater, or 40 m/s or greater. Air flow may be directed down directlyonto the film the hold the film in place, or directed to the sides ofthe oven to create a circulatory or air convection effect. What iscritical to understand is that the film is not part of a larger filmweb, as in casting, and so in theory may be dislodged, depending on thestrength of adhesion of the film, and aerodynamics associated with thewell. But at the same, time, there is greater flexibility in dryingbecause migration of drug in the web is eliminated as an issue.

Infrared, microwave, sonic, ultrasonic and other known methods of dryingmay be employed, either alone or in combination with other methods,including air drying. Such combination approaches may afford moreefficient drying cycles, including reduced temperature, lower heatexposure time, and improved energy efficiency. The sub-well(s) may beheated and may comprise a heater.

Taste Masking

All currently known (and future) methods of taste masking may beemployed, including flavors, sweeteners, bitter masking agents, coatedparticles, ion exchange resins and other methods. A significantadvantage of the present method is that the drug residence time can beminimized.

For example, where the drug is deposited separately from the filmformer, the drug can be completely without solvent. As a non-limitativeexample, drug in an ion exchange complex can be metered into the well,or coated drug particles. This means that the only exposure to water (orother solvent) in the film forming process is the brief period when thedrug is mixed with the film former composition until the solvent isdried.

Preferably, taste masked particles have a particle size with a diameterno greater than the dried height of the film itself. Consideration mayalso be given to mouthfeel. Preferably for mouthfeel particle size isbelow 300 microns, preferably below 200 microns most preferably below100 microns.

It is noted that the deposit method of making films taught herein offersa particular advantage for taste masking, namely, the ability tominimize the time that controlled release drug particles (or complexes)are subject to a solvent.

In the method where the drug active is deposited separately from thefilm former composition, the drug particles (or complexes) are exposedto the solvent used to hydrate the film former for the very brief periodbetween deposit of the drug particles (or complexes) and the time ittakes to substantially remove the solvent by drying. This can have alsoadvantages even where neat drug is used (e.g. to avoid a drug frompartially solubilizing in the solvent and then crystallizing).

Accordingly, total residence time of the drug with liquid solvent may beless than fifteen minutes, preferably less than ten minutes, morepreferably less than five minutes, and most preferably less than twominutes. Such low residence times are also of utility with taste maskedor controlled release drug particles or complexes.

Controlled Release

The term “controlled release” is intended to mean the release of activeat a pre-selected or desired rate. This rate will vary depending uponthe application. Desirable rates include fast or immediate releaseprofiles as well as delayed, sustained or sequential release.Combinations of release patterns, such as initial spiked releasefollowed by lower levels of sustained release of active arecontemplated. Pulsed drug releases are also contemplated. A non limitingexample would be where immediate acting drug is separately depositedtogether with or separate from the film former and a second or thirddeposit of drug with a differing release pattern is added.

In another embodiment, controlled release active is deposited in onepart of the film, and immediate release active is deposited in another(or they may be mixed together). Such embodiments may be combined withshapes that have varying degrees of thickness, or two joined sections(like the shapes discussed in connection with film scoring), or anyother shapes disclosed herein.

Scoring, or partial scoring (weak tear points, with holes and/or reducedthickness) can be employed to ease dose titration, among other reasons.

The polymers that are chosen for the films of the present invention mayalso be chosen to allow for controlled disintegration of the active.This may be achieved by providing a substantially water insoluble filmthat incorporates an active that will be released from the film overtime. This may be accomplished by incorporating a variety of differentsoluble or insoluble polymers and may also include biodegradablepolymers in combination. Alternatively, coated controlled release activeparticles may be incorporated into a readily soluble film matrix toachieve the controlled release property of the active inside thedigestive system upon consumption.

Films that provide a controlled release of the active are particularlyuseful for buccal, gingival, sublingual and vaginal applications. Thefilms of the present invention are particularly useful where mucosalmembranes or mucosal fluid is present due to their ability to readilywet and adhere to these areas. In addition, this invention would allowfor a barrier layer to be metered in the well at some time after theinitial well contents have solidified, thus making a buccal/barrierproduct. Such barrier layer (soluble or insoluble) may also be depositedfirst in certain embodiments.

The convenience of administering a single dose of a medication whichreleases active ingredients in a controlled fashion over an extendedperiod of time as opposed to the administration of a number of singledoses at regular intervals has long been recognized in thepharmaceutical arts. The advantage to the patient and clinician inhaving consistent and uniform blood levels of medication over anextended period of time are likewise recognized. The advantages of avariety of sustained release dosage forms are well known. However, thepreparation of a film that provides the controlled release of an activehas advantages in addition to those well-known for controlled releasetablets. For example, thin films are difficult to inadvertently aspirateand provide an increased patient compliance because they need not beswallowed like a tablet. Moreover, certain embodiments of the inventivefilms are designed to adhere to the buccal cavity and tongue, where theycontrollably dissolve. Furthermore, thin films may not be crushed in themanner of controlled release tablets which is a problem leading to abuseof drugs such as Oxycontin. Furthermore, as mentioned the sequentialnumbering of the unit dose wells allows for identification of a sourceof the abusive drugs, providing the pharmacist notes the identificationindicia during dispensing.

The actives employed in the present invention may be incorporated intothe film compositions of the present invention in a controlled releaseform. For example, particles of drug may be coated with polymers such asethyl cellulose or polymethacrylate, commercially available under brandnames such as Aquacoat ECD and Eudragit E-100, respectively. Solutionsof drug may also be absorbed on such polymer materials and incorporatedinto the inventive film compositions. Other components such as fats andwaxes, as well as sweeteners and/or flavors may also be employed in suchcontrolled release compositions.

Film Thickness

Films are typically understood to be up to 10 mils in thickness (finalproduct as dried), and above ten mils the product is referred to in asheet. For ease of reference, references herein to film are understoodto apply film (sheet) both up to, and beyond 10 mils in thickness. Filmsof the present invention may be 1-200 mils, preferably 3-20 mils, mostpreferably 5 to 15 mils. Thickness may be augmented above the foregoingthicknesses, including without limitation, for dermal use of the endproduct.

Guided Placement

The mold or well becomes the bottom of the final package and onlyrequires the guided placement of a top sheet which completes the packageand the dose unit is merely cut or weakened from the dosage next to it.By guided placement is meant that markers, physical or printed align thetop sheet so that cutting of the final unit dosage unit aligns readilywith the cutter or perforator. In addition, full labeling requirementsmay be resident on the top sheet and bottom wells. In certainembodiments, the top sheet is not gang printed but rather corresponds tothe well or well plurality representing a single carton. Guidedplacement may be achieved using a vision system.

Content Uniformity

The most substantial problem in cast films is the difficulty to have auniform dosage in a film which is cast with the active diluted by alarge number of film formers and other additives plus a time profile forcasting plus the fact that true uniformity is never present in all partsof a cast film. Hence a cast film is dependent on the size of the filmto meet FDA guidelines.

Ideally, as we will see the film forming materials and the active shouldbe deposited from a separate source and into a well of a fixed size.

An aspect of the present invention is adequate mixing of the drug andfilm former composition, not from the perspective of uniformdistribution of drug in the film, but rather adequately containing thedose of the drug within the final dried film matrix. This means thatsubstantially all of the drug is contained within the film matrix inmost embodiments, meaning the drug is substantially subsumed within thefilm. However, in certain embodiments, the drug will be deposited andremain on the top surface of the film, or remain on the bottom surfaceof the film. A polymeric binder may be used when the drug is depositedto ensure that it remains adhered to the film.

Mechanical intervention (Absence of in Film Formation)

Thematically, the Applicants teach low viscosity of the film formercomposition to form a film in the mold or well. This system teaches awayfrom the high viscosities relied upon for content uniformity equilibriumin cast film.

This patent teaches against the main fundamental of prior film art,namely, the use of high viscosity to prevent migration of the active andpreserve uniformity of dose content. Instead, high viscosity here workscontrary to the deposition of the film former's dispersion in the well.Accuracy of the active is instead preserved by the direct depositioninto the well contains the film former.

By mechanical intervention, we mean physical contact with the filmcomposition to spread the film composition, e.g. a three roll coatingapparatus, a doctor blade, or equivalent coating technique.

The high viscosity (and high surface and interfacial tensions) of theprior art (see Watson reference to non-flowing solid/film), requiredmechanical intervention (via the coating apparatus) to apply as a film.The film compositions of the prior art simply lack the spreading or flowcharacteristics to make films deposited in wells.

However, it is contemplated that non mechanical compressed air and/orvibration and/or brief ultrasound may be employed to encourage flow ofthe film composition into a film in the mold or well or surface activeagents to reduce surface tension or substrates to reduce contact angleto promote wetting and spreading of film composition.

In certain, limited embodiments of the present invention, mechanicalintervention may be employed to spread the composition into a filmwithin the well or mold.

Printing/Embossing

Once the film is dry, it is possible to print or emboss an identifier onthe film dosage form. For printing, individual print heads are typicallyrequired. One advantage of the current invention is that printing can betargeted and calibrated in a precise location on the film. Also the wellmay have a chevron such that it leaves an imprint identity on the driedfilm.

The print head is small enough to extend into the well in mostembodiments; ie. the print head dimensions are smaller than the welldimensions. Typically, there is a bank of print heads. As with thefeeder bank, the line may stutter for the print head bank.Alternatively, the identifier may be embossed, either by embossing thedried film, are embossing a logo into the dried film by a shape at thebottom of the well. Such embossment is uniquely possible with films madeby deposit. In other embodiments, an inkjet (or other known method)sprays the identifier onto the film from over the planar surface of thetop of the well.

Multi-layer Films Multi layer films are possible with this methodologysimply by addition depositions of actives, or additional filmcompositions in the manufacturing process. For example, a semi insoluble(or insoluble) backing layer may be separately deposited on a depositedfilm. This may be done after the first layer is dried, or where densityand miscibility will permit separate deposit on non-dried layers, on anon-dried layer. Similarly, a special layer of micro-adhesive,permeation enhancers, or other excipients disclosed herein may bedeposited separately where desired. A multi-layer film with the sameactive in each layer may be formed, where one layer has differentproperties or a carries a controlled release version of the same active.In other embodiments different layers may contain different drugactives.

With films of the present invention, it is possible to make a multilayerfilm wherein one layer has a different shape from the other layer. Forexample, semi-soluble layer without drug might be a square and a drugcontaining film might be deposited on top that dries in a circle.Countless other permutations are possible, in which the shape of onelayer is different from the shape of a second layer, in a multi-layerfilm. Divergence of shape can perform a variety of functions. Forexample, where there is a backing layer in a buccal film, it may bedesired that the backing layer extends past the drug containing layerthat is against the buccal mucosa.

Covering the Mold or Well

It is contemplated that the mold or well will be covered and sealed aspart of a continuous manufacturing process. It is important then thatconsideration be given relative to ambient humidity prior to sealing themold or well to avoid bringing excess moisture into the package. It maybe desirable to cool the film containing well or mold, or use othermethod (compressed air, nitrogen or other gas) to reduce humidity priorto packaging.

Various forms of guided placement may be employed to ensure alignment ofthe mold or well with the top covering. In other embodiments, guidedplacement is not needed, particularly where the top covering is gangprinted.

The top covering will typically be foil, aclar, or other suitable sheetlike material with suitable barrier properties to ensure stability ofthe product for the intended area of use (see ICH global guidelines).

The wells may be filled with nitrogen or other gas (other than ambientair) prior to sealing.

The final package may be child resistant, meaning the well and topsheetprimary package may be child resistant. Alternatively, the primarypackage may be placed in a child resistant outer container or package.In a crude embodiment, a flexible blister of films may be placed in achild resistant bottle, or placed in child resistant outer where theblister is anchored or attached to the child resistant outer.

The molds or wells may be joined together in a group of packages or maybe separated. Such separation may occur at the time of filling/depositor later, i.e. after drying.

The Dried Film Thematically, film formation by deposit presents muchmore flexibility than conventional wet casting. This is because inconventional wet casting, uniform distribution of active within the filmis necessary so that when cut into final pieces the individual filmdoses will meet drug content label claims.

In contrast, here the desired level of drug is accurately metered intothe mold or well along with the film former composition. Drug migrationor agglomeration is not really an issue.

The dried film must have only minimal mechanical strength to allow it tobe released from the mold or well. A given film formulation's propensityto elongation is acceptable. Tensile strength and elasticity may beminimal.

The dried film must simply be strong enough for release and use by theconsumer.

Issues like surface mottle, or voids do not represent drug contentdefects, and so are judged on the basis of consumer acceptability.

The dried film of the present invention preferably has less than 10%variability in height (measured from the thickest portion of the film tothe thinnest portion, measured vertically). In certain embodiments,additional variability may be acceptable or preferred for a wedged ortapered shape.

Preferably, substantially all of the drug is contained within the driedfilm matrix in most embodiments. However, in certain embodiments, thedrug will be deposited and remain on the top surface of the film, orremain on the bottom surface of the film.

Films made by deposit may comprise non-homogeneous liquid phases, suchas emulsions, or loose gels exhibiting syneresis or liquid crystallinemesomorphic phases may also be made by deposit. Films made with suchattributes may yield film with unusual visual appearance and textures.Such unusual textures may promote rapid disintegration and or rapidabsorption of the drug actives contained therein.

Moisture Levels

In the case of wet cast films, there is an spoken adage: “the wetter thebetter.” What this means is that relatively high moisture content isassociated with easy-to-process films, bearing in mind the mechanicalproperties required in wet casting, which includes rolling the driedfilm onto itself to form a roll after drying. As a practical matter, wetcast films that are commercially manufactured have a moisture level of7-10%.

By commercially manufactured, we mean a product made in a batch size ofat least 100,000 doses. Films may be cast with lower moisture levels,but this is typically performed at bench scale, where the films are notrolled onto themselves but simply dried in an oven after casting (andleft essentially flat on the substrate on which they were cast).

Films of the deposit method may be dried to a lower moisture level, i.e.a solvent (typically water) content of less than 10%, preferably lessthan 5%, and even more preferable below 3%. It is possible to dry filmsof the deposit level to a moisture level of below 2%.

Films of the deposit method, manufactured at commercial scale, may bedried to a solvent (typically water) content of 2-6%, or a higher rangeof 3-5%.

These low moisture levels have applicability for improved shelf lifeduration, as well as for actives that are particularly sensitive tomoisture levels, for example and without limitation, certain vaccines,certain proteins, and other active and bioactive substances.

Film by deposit enables the manufacture of films with lower moisturecontent than commercial wet casting; film by deposit may also be used inrare instances to make films with higher moisture content thancommercial wet cast films.

It is not practicable in commercial wet cast films to exceed certainmoisture levels because the “wet” dried film will tend to adhere to bothsurfaces when rolled onto itself. Excessive tack and stickiness makethis impracticable.

However, in film by deposit, in special cases where high moisturecontents are desired, it is possible to “dry” the commercialmanufactured film to 10% solvent (water) or greater, 12.5% or greater,15% or greater, or even as much as 20% solvent (water), or greater. Infilm be deposit, moisture content may be 12.5% to 25%, or 15% to 20%.Such high moisture films may have moisture domains within the film. Somefilms will have a gel-like center. Such high moisture films may besingle layer, or multilayer. Such films may have unique applicationwhere, for stability or bioavailability reasons, the active is intendedto be dissolved in, or in close proximity or contact to moisture.

The level of moisture in the film prior to sealing the blister well maybe measured in-line within the well using a non-contact probe such as anear infrared (NIR) probe.

Pre-Releasing the Film

In some embodiments, it may be desirable to take steps to pre-releasethe film from the bottom of the mold or well (such pre-release may be inwhole or in part). For example, a roller may be employed with a surfacethat promotes release of the film from the bottom of the mold or well.Multiple rollers may be employed to crinkle the well (or a plurality ofwells), pushing the well up from its formed shape and thereby helping torelease the film. The film package may be bent lengthwise, or sidewise.The wells may be bent and unbent by the rollers. For example, as shownin FIG. 14, a sheet 1 with a plurality of wells 2 containing the film,which may be a single layer film or, as shown in FIG. 14 by way ofexample only a multilayer film 12, 13, and top sheet or covering 17 isbent and unbent around rollers 18, 19 to promote release of the driedfilm. In some embodiments, there is a top and bottom roller (or one ormore) simultaneously operating on the wells. One or more roller haveprotrusions, or a rough surface to facilitate release.

Other methods may be employed to physically disturb the well to promoterelease of the dried film.

This step may occur prior to, or after, the covering 17 is placed in topof the mold or the well. The purpose is to make it easier for thepatient to remove the film from the mold or well for use. Vacuum mayalso be employed for this purpose.

In other embodiments, the consumer pre-releases the film by pushing aconvexity in the well into a concavity (where the well is formed with aconvexity for this purpose). Other methods are discussed herein. Whereastypical blister wells have sharp angles of almost 90 degrees from theweb axis, wells designed for deposition may have much shallower angles.Angles may be from 15-75 degrees or more preferably 30-60 degrees ormost preferably 40-50 degrees. The angled wells allow the eversion ofthe well structure by pushing the well from below to change the wellbottom from concave to convex, allowing the film to be easily removedfrom the convex well bottom. The well walls may also have convex orconcave curvature to facilitate eversion.

Mechanical Intervention to Release

Occasionally, it may be desirable to employ a particular formulationthat when combined with a certain well or mold material experiencessubstantial adhesion after drying, thereby creating a release issue.

In such instances, it may be desirable to employ a mechanicalintervention to assist in releasing the film, in whole or in part, fromthe well or mold surface. This can be performed using a blade, a scraperor analogous physical apparatus, suction, compressed air, or othermethod. Such intervention may be performed in conjunction with, andoptionally contemporaneously with, the methods described above(Pre-Releasing the Film) and below (Release through IntentionalCrystallization).

Release through Intentional Crystallization

One method to effect a release, or partial release, or easing of releaseis through an intentional crystallization of the film that manifests onthe outer surfaces of the film. Typically, such crystallization would beavoided. However, where film is made by deposit, and is formed on thewell as a substrate, it can be desirable to intentionally include one ormore crystallization components that will crystallize, and physicallypush the film off (or partially off of) the bottom of the well. This canpromote release of the film from the bottom of the well.

Suitable crystallization components may include without limitation:erythritol, xylitol, mannitol, sucrose and citric acid.

Suitable crystallization components may be included in effectiveamounts. Sample ranges (measured from dry weight of the film) include:1-30% or more preferably 3-20% or most preferably 5-10%, or 5-15%.

Storage to Promote Release

With conventional wet cast film, the film is delaminated from thecoating substrate prior to packaging. While it is sometimes possible todetermine visually the “top” side of the film (i.e. the top side when itwas dried), insofar as the film as been de-laminated from its coatingsubstrate there is not a meaningful film top- and bottom with respect tothe foil pouch the film is typically packaged into. In contrast, a filmmade by deposit in a well or mold clearly has an identifiable “bottom.”One method to promote release of the film is to store the film wellsupside down in the carton and store cartons (e.g. when palletized) tomaintain this same upside-down posture. This method may be particularlyemployed where the top sheet is not in contact with the dried film whenthe top sheet is first applied.

The film is held upside for a certain duration prior to release, e.g. atleast seven days, at least fourteen days, at least thirty days. In thisway, upside storage can be validated for product release specifications.It is also possible to palletize the film with boxes pointed downwards,again to encourage release. Such palletization ensures that the productis facing downwards in distribution.

Other methods may be used to effect release the film from the wellsubstrate such as temperature cycling by subjecting the blisters to oneor more alternating cycles of refrigeration or freezing followed bythawing to room temperature.

Film-Forming Polymers

The non limiting polymer may be water soluble, water swellable, waterinsoluble, or a combination of one or more either water soluble, waterswellable or water insoluble polymers. These may include homopolymers orvarious molecular weights or co-polymers of varying fractions ordifferent polymer units. The polymer may include cellulose or acellulose derivative. Specific examples of useful water soluble polymersinclude, but are not limited to, pullulan, hydroxypropylmethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodiumalginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum,acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer,polyvinyl alcohol—polyethylene glycol copolymers, carboxyvinylcopolymers, starch, gelatin, pectin and combinations thereof. Specificexamples of useful water insoluble polymers include, but are not limitedto, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetatephthalate, hydroxypropyl methyl cellulose phthalate and combinationsthereof.

As used herein the phrase “water soluble polymer” and variants thereofrefer to a polymer that is at least partially soluble in water, anddesirably fully or predominantly soluble in water, or absorbs water.Polymers that absorb water are often referred to as being waterswellable polymers. The materials useful with the present invention maybe water soluble or water swellable at room temperature and othertemperatures, such as temperatures exceeding room temperature. Moreover,the materials may be water soluble or water swellable at pressures lessthan atmospheric pressure. Desirably, the water-soluble polymers arewater soluble or water swellable having at least 20 percent by weightwater uptake. Water swellable polymers having a 25 or greater percent byweight water uptake are also useful. Films or dosage forms of thepresent invention formed from such water-soluble polymers are desirablysufficiently water soluble to be dissolvable upon contact with bodilyfluids.

Other polymers useful for incorporation into the films of the presentinvention include, but are not limited to, biodegradable polymers,copolymers, block polymers and combinations thereof. Among the knownuseful polymers or polymer classes which meet the above criteria are:poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxanoes,polyoxalates, poly(.alpha.-esters), polyanhydrides, polyacetates,polycaprolactones, poly(orthoesters), polyamino acids,polyaminocarbonates, polyurethanes, polycarbonates, polyamides,poly(alkyl cyanoacrylates), and mixtures and copolymers thereof.Additional useful polymers include, stereopolymers of L- and D-lacticacid, copolymers of bis(p-carboxyphenoxy)propane acid and sebacic acid,sebacic acid copolymers, copolymers of caprolactone, poly(lacticacid)/poly(glycolic acid)/polyethyleneglycol copolymers, copolymers ofpolyurethane and (poly(lactic acid), copolymers of polyurethane andpoly(lactic acid), copolymers of .alpha.-amino acids, copolymers of.alpha.-amino acids and caproic acid, copolymers of .alpha.-benzylglutamate and polyethylene glycol, copolymers of succinate andpoly(glycols), polyphosphazene, polyhydroxy-alkanoates and mixturesthereof. Binary and ternary systems are contemplated.

Other specific, but non limiting, polymers useful include those marketedunder the Medisorb and Biodel trademarks. The Medisorb materials aremarketed by the Dupont Company of Wilmington, Del. and are genericallyidentified as a “lactide/glycolide co-polymer” containing “propanoicacid, 2-hydroxy-polymer with hydroxy-polymer with hydroxyacetic acid.”Four such polymers include lactide/glycolide 100 L, believed to be 100%lactide having a melting point within the range of 338°−347° F.(170°−175° C.); lactide/glycolide 100 L, believed to be 100% glycolidehaving a melting point within the range of 437°−455° F. (225°−235° C.);lactide/glycolide 85/15, believed to be 85% lactide and 15% glycolidewith a melting point within the range of 338°−347° F. (170°−175° C.);and lactide/glycolide 50/50, believed to be a copolymer of 50% lactideand 50% glycolide with a melting point within the range of 338°−347° F.(170°−175° C.).

The Biodel materials represent a family of various polyanhydrides whichdiffer chemically.

Generally, lower molecular weight polymer grades will be favored forcertain embodiments of the present invention, as they will make lowerviscosity film former compositions.

Such lower molecular weight grades will generally disintegrate fasterthan higher molecular weight grades. Where longer disintegration timesare desired, it may be desirable to include non-water-soluble polymers.

Suitable Excipients

Any suitable excipient known in the art may be using in compositions ofthe present invention. Apart from film formers, a non-limiting listincludes, pH buffers, permeation enhancers, surfactants, viscosityreducing agents, wetting agents, de-gassing agents, gassing agents,flavors, bitter masking agents, plasticizers, anti-caking agents,co-solvents, antioxidants and any other known excipient.

Excipients may be included in sufficient or effective amounts.

As discussed above, excipients may be added with the film formercomposition, or the drug (where the two are deposited separately).

Solvents

The following is a non-limiting list of solvents that may be employed:water, ethanol, acetone, DMSO, isopropanol, glycerol, propylene glycol,polyethylene glycol, propylene carbonate, ethyl acetate, d-limonene.

pH Buffers

Buffering agents may be used to control pH (acidic or base), includingwithout limitation, sodium bicarbonate, potassium bicarbonate, sodiumcarbonate, potassium carbonate, calcium carbonate, dipotassiumphosphate, potassium citrate, sodium phosphate, Formic Acid/SodiumFormate, Hydrogen Chloride/Potassium Chloride, HydrogenChloride/Glycine, Hydrogen Chloride/Potassium Hydrogen Phthalate, CitricAcid/Sodium Citrate, Acetic Acid/Sodium Acetate, Citric Acid/DisodiumHydrogen Phosphate, Citric Acid/Trisodium Citrate Dihydrate, etc., andany other such buffer system.

The buffer system may be designed to dynamically control the pH of theproduct taking into consideration the effect of saliva during use, i.e.,a dynamic buffer system. Non limitative, examples of buffer systems toobtain a pH include dibasic sodium phosphate and monobasic sodiumphosphate. Both are FDA accepted buffer materials used and listed in theinactive ingredients list.

For example, for a pH of 7, the ratio of monobasic/dibasic can be4.6/8.6; for a pH of 7.5 the ratio of monobasic/dibasic can be 1.9/11.9;and for a pH of 8.0 the ratio of monobasic/dibasic can be 0.6/13.4.These are mathematically calculated buffer numbers and will need to beadjusted according to the other ingredients added to the formula.

They also need to be adjusted for the length of time designed for thedissolution of the dosage unit on the buccal mucosa since saliva can beof a pH of about 6.8 but as it is made in larger amounts in the mouththe pH of saliva can sometimes become more basic. Thus, this dynamicbuffer range is adjusted in the dosage unit by the amount s of thebuffer system since saliva is freshly renewable in the mouth. See FuiszU.S. Patent Application Publication Nos. 2009/0098192 A1 and US2011/0318390 A1 discussing dynamic buffering and incorporated herein byreference. The dynamic buffer systems of the present invention may beacidic or basic.

Fillers

Fillers may be useful to increase the percentage of solids in theformulation and reduce solvent requirement allowing for more rapidevaporation and faster throughput. Fillers may be soluble of insoluble.Non-limiting examples are polydextrose, maltodextrin, inulin,microcrystalline cellulose.

Surfactants

Surfactants may be useful in connection with the present invention toreduce surface tension. Reducing surface tension is helpful to promoteflowability of the film composition (see Young Equation discussedabove), and may also be useful to promote mixing of the film formercomposition with separately added drug.

Non limiting surfactants may include non-ionic surfactants, like polyolesters (e.g. glycol or glycerol esters, sorbitan derivatives);polyoxyethylene esters (e.g. polyethylene glycol (the “PEGs”; andpoloxamers. Common ionic surfactants include ethers of fatty alcohols.

Any suitable surfactant may be employed.

In the approach of Yang et al, too much surfactant will create a productwith a contact angle that is too low (Young's Equation) for coating onthe substrate. Here, the formulator will want to use more surfactant todecrease the contact angle and promote flowability.

Permeation Enhancers

The film made by deposit may comprise one or more penetration agents,i.e., a substance that enhances absorption through the mucosa, mucosalcoating and epithelium (otherwise known (see U.S. Patent ApplicationPublication No. 2006/0257463 A1, the content of which is incorporatedherein by reference) as a “penetration enhancer” or “permeabilityenhancer”). The penetration agent may comprise but is not limited topolyethylene glycol (PEG), diethylene glycol monoethyl ether(Transcutol), 23-lauryl ether, aprotinin, azone, benzalkomin chloride,cetylperidium chloride, cetylmethylammonium bromide, dextran sulfate,lauric acid, lauric acid/propylene glycol, lysophosphatilcholine,menthol, methoxysalicylate, oleic acid, phosphaidylcholine,polyoxyethylene, polysorbate 80, sodium EDTA, sodium glycholated, sodiumglycodeoxycholate, sodium lauryl sulfate, sodium salicylate, sodiumtaurocholate, sodium taurodeoxycholate, sulfoxides, and various alkylglycosides or, as described in U.S. Patent Application Publication No.2006/0257463, bile salts, such as sodium deoxycholate, sodiumglycodeoxycholate, sodium taurocholate and sodium glycocholate,surfactants such as sodium lauryl sulfate, polysorbate 80, laureth-9,benzalkonium chloride, cetylpyridinium chloride and polyoxyethylenemonoalkyl ethers such as the BRIJ® and MYRJ® series, benzoic acids, suchas sodium salicylate and methoxy salicylate, fatty acids, such as lauricacid, oleic acid, undecanoic acid and methyl oleate, fatty alcohols,such as octanol and nonanol, laurocapram, the polyols, propylene glycoland glycerin, cyclodextrins, the sulfoxides, such as dimethyl sulfoxideand dodecyl methyl sulfoxide, dodecyl maltoside, tetradecyl maltoside,the terpenes, such as menthol, thymol and limonene, urea, chitosan andother natural and synthetic polymers. Preferably, the penetration agentis a polyol, e.g., polyethylene glycol (PEG), glycerin, maltitol,sorbitol etc. or diethylene glycol monoethyl ether (Transcutol)),d-α-Tocopheryl polyethylene glycol 1000 succinate (vitamin E-TPGS),Aprotinin, Ceramides, Decanoyl carnitine, Lauric acid, Lauroylcarnitine, Lysophosphatidylcholine, Poloxamer 407, Poloxamer F68.

Preferably, the dried film composition may comprise 0.01% to 10%permeation enhancer by mass, more preferably 0.1% to 5%.

Viscosity Reducing Agents

Various agents may be employed to reduced viscosity. In particular andwithout limitation, hydrophobic salts may serve to reduce viscosity,which is of use in connection with the film former composition. Withoutlimitation, the following agents have been found useful: argininehydrochloride, sodium thiocyanate, ammonium thiocyanate, ammoniumsulfate, ammonium chloride, calcium chloride, zinc chloride, or sodiumacetate. The teaching of US 20150071925, hereby incorporated herein byreference as if fully stated. Organic esters may also be useful. See US20150071925, hereby incorporated herein by reference as if fully stated.

Effective amounts are used.

Anti-Caking Agents

Anti-Caking Agents are particularly useful where the drug active isadded separately from the firm former composition in powder orparticulate form.

Moisture, pressure and temperature all adversely affect powdered andgranulated products. These conditions can make products cake, lump,bridge, clog equipment and cause fib and performance problems.Anti-caking and Free-flow powder agents can improve the flow behaviorand storage stability of a broad variety of food products.

Silica derived materials are preferred.

A non limitative list includes: tricalcium phosphate, powderedcellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide,potassium ferrocyanide, calcium ferrocyanide, bone phosphate, sodiumsilicate, silicon dioxide, calcium silicate, magnesium trisilicate,talcum powder, sodium aluminosilicate, potassium aluminium silicate,calcium aluminosilicate, calcium carbonate, bentonite, aluminiumsilicate, stearic acid, and polydimethylsiloxane.

Effective amounts are employed for reliable flow of powder/particulate.

Pharmaceutical Actives (also referred to herein as active pharmaceuticalingredients or drugs)

By the term pharmaceutical active agent, we mean a drug as describedbelow. By pharmaceutical active agent composition, we mean anycomposition containing one or more pharmaceutical active agents.However, it is expressly contemplated that the compositions and methodstaught herein are not limited to drugs but may include any active agentas more fully described below.

The active agents that may be incorporated into the films of the presentinvention include, without limitation bioactive agents such aspharmaceutical active agents, vaccines, cosmetic active agents, drugs,medicaments, botanicals, antigens or allergens such as ragweed pollen,spores, microorganisms, plant actives, enzymes and vitamins, as well asother active agents such as seeds, mouthwash components, flavors,fragrances, preservatives, sweetening agents, colorants, spices, andcombinations thereof. An active agent composition is a compositioncontaining one or more of the active agents described herein.

A wide variety of non-limiting medicaments, bioactive active substancesand pharmaceutical compositions may be included in the dosage forms ofthe present invention.

Examples of useful drugs include ace-inhibitors, antianginal drugs,anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, analgesics,anesthetics, anti-convulsants, anti-depressants, anti-diabetic agents,anti-diarrhea preparations, antidotes, anti-histamines,anti-hypertensive drugs, anti-inflammatory agents, anti-lipid agents,anti-manics, anti-nauseants, anti-stroke agents, anti-thyroidpreparations, anti-tumor drugs, anti-viral agents, acne drugs,alkaloids, amino acid preparations, anti-tussives, anti-uricemic drugs,anti-viral drugs, anabolic preparations, systemic and non-systemicanti-infective agents, anti-neoplastics, anti-parkinsonian agents,anti-rheumatic agents, appetite stimulants, biological responsemodifiers, blood modifiers, bone metabolism regulators, cardiovascularagents, central nervous system stimulates, cholinesterase inhibitors,contraceptives, decongestants, dietary supplements, dopamine receptoragonists, endometriosis management agents, enzymes, erectile dysfunctiontherapies, fertility agents, gastrointestinal agents, homeopathicremedies, hormones, hypercalcemia and hypocalcemia management agents,immunomodulators, immunosuppressives, migraine preparations, motionsickness treatments, muscle relaxants, obesity management agents,osteoporosis preparations, oxytocics, parasympatholytics,parasympathomimetics, prostaglandins, psychotherapeutic agents,respiratory agents, sedatives, smoking cessation aids, sympatholytics,tremor preparations, urinary tract agents, vasodilators, laxatives,antacids, ion exchange resins, anti-pyretics, appetite suppressants,expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatorysubstances, coronary dilators, cerebral dilators, peripheralvasodilators, psycho-tropics, stimulants, anti-hypertensive drugs,vasoconstrictors, migraine treatments, antibiotics, tranquilizers,anti-psychotics, anti-tumor drugs, anti-coagulants, anti-thromboticdrugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants,neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid andanti-thyroid preparations, diuretics, anti-spasmodics, uterinerelaxants, anti-obesity drugs, erythropoietic drugs, anti-asthmatics,cough suppressants, mucolytics, DNA and genetic modifying drugs, andcombinations thereof.

Examples of medicating active ingredients contemplated for use in thepresent invention include antacids, H₂-antagonists, and analgesics. Forexample, antacid dosages can be prepared using the ingredients calciumcarbonate alone or in combination with magnesium hydroxide, and/oraluminum hydroxide. Moreover, antacids can be used in combination withH₂-antagonists.

Analgesics include opiates and opiate derivatives, such as oxycodone(available as Oxycontin®), ibuprofen, aspirin, acetaminophen, andcombinations thereof that may optionally include caffeine.

Other preferred drugs for other preferred active ingredients for use inthe present invention include anti-diarrheals such as immodium AD,anti-histamines, anti-tussives, decongestants, vitamins, and breathfresheners. Common drugs used alone or in combination for colds, pain,fever, cough, congestion, runny nose and allergies, such asacetaminophen, chlorpheniramine maleate, dextromethorphan,pseudoephedrine HCl and diphenhydramine may be included in the filmcompositions of the present invention.

Also contemplated for use herein are anxiolytics such as alprazolam(available as Xanax®); anti-psychotics such as clozopin (available asClozaril®) and haloperidol (available as Haldol®); non-steroidalanti-inflammatories (NSAID's) such as dicyclofenacs (available asVoltaren®) and etodolac (available as Lodine®), anti-histamines such asloratadine (available as Claritin®), astemizole (available asHismanal™), nabumetone (available as Relafen®), and Clemastine(available as Tavist®); anti-emetics such as granisetron hydrochloride(available as Kytril®) and nabilone (available as Cesamet™);bronchodilators such as Bentolin®, albuterol sulfate (available asProventil®); anti-depressants such as fluoxetine hydrochloride(available as Prozac®), sertraline hydrochloride (available as Zoloft®),and paroxtine hydrochloride (available as Paxil®); anti-migraines suchas Imigra®, ACE-inhibitors such as enalaprilat (available as Vasotec®),captopril (available as Capoten®) and lisinopril (available asZestril®); anti-Alzheimer's agents, such as nicergoline; andCa.sup.H-antagonists such as nifedipine (available as Procardia® andAdalat®), and verapamil hydrochloride (available as Calan®).

Erectile dysfunction therapies include, but are not limited to, drugsfor facilitating blood flow to the penis, and for effecting autonomicnervous activities, such as increasing parasympathetic (cholinergic) anddecreasing sympathetic (adrenersic) activities. Useful non-limitingdrugs include sildenafils, such as Viagra®, tadalafils, such as Cialis®,vardenafils, apomorphines, such as Uprima®, yohimbine hydrochloridessuch as Aphrodyne®, and alprostadils such as Caverject®.

The popular H₂-antagonists which are contemplated for use in the presentinvention include cimetidine, ranitidine hydrochloride, famotidine,nizatidien, ebrotidine, mifentidine, roxatidine, pisatidine andaceroxatidine.

Active antacid ingredients include, but are not limited to, thefollowing: aluminum hydroxide, dihydroxyaluminum aminoacetate,aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodiumcarbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuthsubcarbonate, bismuth subgallate, bismuth subnitrate, bismuthsubsilysilate, calcium carbonate, calcium phosphate, citrate ion (acidor salt), amino acetic acid, hydrate magnesium aluminate sulfate,magaldrate, magnesium aluminosilicate, magnesium carbonate, magnesiumglycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate,milk solids, aluminum mono-ordibasic calcium phosphate, tricalciumphosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate,magnesium aluminosilicates, tartaric acids and salts.

The pharmaceutically active agents employed in the present invention mayinclude allergens or antigens, such as, but not limited to, plantpollens from grasses, trees, or ragweed; animal danders, which are tinyscales shed from the skin and hair of cats and other furred animals;insects, such as house dust mites, bees, and wasps; and drugs, such aspenicillin.

Botanicals may be employed, including marijuana, tobacco and anyderivative thereof, including tetrahydrocannabinol and cannabidiol).Nicotine salts may be employed. Such botanicals may or may not beapproved for pharmaceutical use or otherwise understood to bepharmaceutically active.

Active agents may include proteins such as, enzymes and antibodies orother biologics such as (and without limitation) live attenuated andinactive viruses or other antigenic material for use as vaccines or drugdelivery agents or nucleotide-based vaccines consisting of DNA, RNA orplasmids

An anti-oxidant may also be added to the film to prevent the degradationof an active, especially where the active is photosensitive.

Cosmetic active agents may include breath freshening compounds likementhol, other flavors or fragrances, especially those used for oralhygiene, as well as actives used in dental and oral cleansing such asquaternary ammonium bases. The effect of flavors may be enhanced usingflavor enhancers like tartaric acid, citric acid, vanillin, or the like.Anti-tartar agents for dental use may also be employed.

Coloring Agents

Also color additives can be used in preparing the films. Such coloradditives include food, drug and cosmetic colors (FD&C), drug andcosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).These colors are dyes, their corresponding lakes, and certain naturaland derived colorants. Lakes are dyes absorbed on aluminum hydroxide.

Other examples of coloring agents include known azo dyes, organic orinorganic pigments, or coloring agents of natural origin. Inorganicpigments are preferred, such as the oxides or iron or titanium, theseoxides, being added in concentrations ranging from about 0.001 to about10%, and preferably about 0.5 to about 3%, based on the weight of allthe components.

Flavors Flavors may be chosen from natural and synthetic flavoringliquids. An illustrative list of such agents includes volatile oils,synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins orextracts derived from plants, leaves, flowers, fruits, stems andcombinations thereof. A non-limiting representative list of examplesincludes mint oils, cocoa, and citrus oils such as lemon, orange, grape,lime and grapefruit and fruit essences including apple, pear, peach,grape, strawberry, raspberry, cherry, plum, pineapple, apricot or otherfruit flavors.

The films containing flavorings may be added to provide a hot or coldflavored drink or soup.

These flavorings include, without limitation, tea and soup flavoringssuch as beef and chicken.

Other useful flavorings include aldehydes and esters such asbenzaldehyde (cherry, almond), citral i.e., alphacitral (lemon, lime),neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon),aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehydeC-12 (citrus fruits), tolyl aldehyde (cherry, almond),2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus, mandarin),combinations thereof and the like.

The sweeteners may be chosen from the following non-limiting list:glucose (corn syrup), dextrose, invert sugar, fructose, and combinationsthereof; saccharin and its various salts such as the sodium salt;dipeptide sweeteners such as aspartame; dihydrochalcone compounds,glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives ofsucrose such as sucralose; sugar alcohols such as sorbitol, mannitol,xylitol, isomalt and the like. Also contemplated are hydrogenated starchhydrolysates and the synthetic sweetener3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide,particularly the potassium salt (acesulfame-K), and sodium and calciumsalts thereof, and natural intensive sweeteners, such as Lo Han Kuo.Other sweeteners may also be used. Sweeteners may be employed from 1% to50%, preferably 10-35%, more preferably 20-30% of the composition (byweight or mass) Isomalt is particularly useful with certain embodimentsof the present invention insofar as it resists crystallization when madewith compositions suitable for forming films by the deposit methodstaught herein. Moreover, isomalt is thermally and chemically stable withlow hygroscopicity.

When the active is combined with the polymer in the solvent, the type ofmatrix that is formed depends on the solubilities of the active and thepolymer. If the active and/or polymer are soluble in the selectedsolvent, this may form a solution. However, if the components are notsoluble, the matrix may be classified as an emulsion, a colloid, or asuspension.

Transdermal Films

In certain embodiments, the deposit method of the present invention maybe used to make transdermal films. Since transdermal films are typicallymultilayer, different layers may be deposited in series, if necessarybetween drying intervals. Backing layers of materials not readilydepositable may be inserted into the mold or well (including inter aliamicroneedles). The following patents, describing transdermalcompositions, are incorporated by reference as if fully stated herein(including incorporations into such patents): U.S. Pat. No. 9,089,527 B2(assigned to Lohmann); U.S. Pat. No. 8,696,637 (assigned to Lohmann);U.S. Pat. No. 6,117,448 (assigned to Lohmann); U.S. Pat. No. 5,820,876(assigned to Lohmann). Obviously, different compositions, and differentexcipients are used in transdermal systems from oral soluble films andso the teaching of the incorporated patents is important for suchembodiments.

EXAMPLES

A number of template molds were made, 10 mil recess thick, and adheredto a Teflon sheet. The compositions are shown in Table 1A, and Table 2Aand Table 3. Results after deposit and drying for the compositions ofTable 1A and Table 2A, are found in Tables 1B and 2B, respectively.

As the results in Table 1B demonstrate, the compositions described inTable 1A were generally too viscous and exhibited too much surfacetension to adequately flow into a mold.

A number of the examples of 2A successfully flowed into films, andcertain examples demonstrated good embedding of solids. For example,sample D of Table 2A showed good embedding of calcium carbonateparticulate, which was used as a “dummy” drug particulate. Theflowability of these examples would preclude their ability to be coatedusing conventional wet casting techniques. Their very proclivity to flowwould lead them to roll off the substrate in a conventional castingprocess.

The compositions of Table 3 are non-aqueous. Sample NA4, comprising29.7% PEO (300,000) and 70.3% PEG400 is a promising approach for a slowrelease film of the present invention. Applicants observed that a rangeof 20-40% PEO (300,000 mw and above), together with PEG 80 as a solventmay be an attractive formulation option where slow release is desiredfrom a film made by the deposit method.

Table 4 contains surface tension values.

TABLE 1A Aqueous Evaluation Samples HPMC HPMC Sample ID Instagel CornStarch K15M F50 HPC PVP PG PEG2000 1 1.45% 1.99% 2 9.15% 3 4.32% 6.81%4.48% 8.16% 4 3.74% 5.79% 2.23% 6.83% 5 2.57% 1.05% 6   5% 7 1.25% 81.00% 9 1.86% 10 0.90%

TABLE 1B Aqueous Evaluation Samples Post Thermal Treatment Sample IDPass Fail Cause 1 x high contact angle on silicon mold, did not wet orspread, did not embed solids, does not disperse in water 2 x highcontact angle on silicon mold, did not wet or spread, did not embedsolids, does not disperse in water 3 x too viscous 4 x very viscous,produced thick film that did not disperse readily in water 5 x film verythin and brittle, poor wetting and spreading on substrate, strongadhesion to teflon substrate when dried 6 x too viscous 7 x film toobrittle and too thin 8 x film too brittle and too thin 9 x too viscousto add to template 10  x too viscous to add to template

TABLE 2A Aqueous PEO Film Former Compositions Sample ID PEO 100K PEO300K PEO 900K PEG400 PG PS 20 Viscosity cps A 9.09% 18.18% B 10.58% 6.68% 331* C 10.59%  7.30% 366* D 10.69%  5.59% 306* E  4.76% F 6.52%12.90% 1.65% G 5.71%  3.50%  2243-1261** H 5.79%  4.05% I 18.31%  7.44% 1846-1155** J 18.31%  8.80% K 12.38%  4.45% 413* L 10.53%  5.61% M 7.06% 1.77%  5.60% N 4.76%  653-468** O 3.67% 217* P 6.28% *Newtonianfluid viscosity **Non-Newtonian fluid viscosity range from 10 to 100 s⁻¹

TABLE 2B Aqueous PEO Film Former Post Thermal Treatment EvaluationsSample ID Pass Fail Cause A x films .2 mm think easily disperse in waterB x good spreading and wetting, low viscosity C x good spreading andwetting, low viscosity D x film former added to calcium carbonate, goodembedding of solids E x viscous, but good spreading and wetting, thinfilm easily disperses in water F x viscous, films .15 mm, easilydisperse in water G x x viscous composition, can produce good thin film,readily dispersible in water H x x viscous composition, can produce goodfilm, easily dispersible in water I x too viscous, thick film, noteasily dispersible in water J x too viscous, thick film, not easilydispersible in water K x good spreading and wetting, low viscosity L xgood spreading and wetting, low viscosity M x good spreading andwetting, low viscosity N x produced film with good dissolution in waterO x produced thin film with good dissolution in water P x produced thinfilm easily dispersible in water

TABLE 3 Non-Aqueous PEO Compositions Post Thermal Treatment 90° C.Sample ID PEO100K PEO300K PEG400 Pass Fail Cause NA1 8.88% 91.12% xlacks cohesion, waxy dispersion NA2 9.51% 90.49% x lacks cohesion, waxydispersion NA3 10.22% 89.78% x weak, wet, thick (1.23 mm) and fragilefilm; poor dissoution in water NA4 29.70% 70.30% x x viscous dispersion,poor flowability, opaque thick (1.6 mm) strong film; slow dissolution inwater, tacky vehicle when wet

TABLE 4 Examples of Surface Tension Values Temp □ ° C. mN/m Water 2571.97 40 69.56 80 62.6 PEG200 20 43.5 ISP 25 23

Example AA

The film of Example AA is a relatively slow-dissolving film, i.e. morethan 10 minutes in the oral cavity of a user to dissolve.

The table below sets forth the ingredients of the film of Example AA.

Ingredients % Amount Klucel LF 18 4.5 PEO N 10 2.5 0.625 Natrosol 250 L50.075 12.51875 PVA 2.5 0.625 Carbopol 934P 0.5 0.125 Magnasweet 0.30.075 Sucralose 0.75 0.1875 Sodium Benzoate 0.375 0.09375 Total: 100 25% Solids 20 20 Total weight 500 125 Water Amt 400 100

Klucel LF is hydroxypropylcellulose; PEO N 10 is polyethylene oxide,polyox WSR N 10; Natrosol 250 L is hydroxyethylcellulose, natrosol 250L; Kollicoat Protect is polyethylene glycol polyvinyl alcohol copolymer;PVA is polyvinyl alcohol; Carbopol 934P is carbomer, Carbopol 934P;Magnasweet is monoammonium glycyrrhizinate, Magnasweet MM 100.

The above composition was mixed and made into several circular-shapedfilms by deposit. The films were flexible and non-tacky. They were thin,strong (good tensile strength) and appeared to be well suited for theirintended application. They were easily removable from the carrier stripswithout breakage and held up well to handling. The films appeared to bea composite of several liquid phases, solids, and aeration.

The films were examined under both transmitted and dark field surfaceillumination with cross polarizers. There was evidence of liquidcrystalline mesomorphic phases and this phase appeared to be distributedthroughout the film. Further, it appeared that interfaces within thefilm are coated. Under some conditions, these phases could promote rapidoromucosal absorption of drugs incorporated therein.

With transmitted light, again under cross polarization, the dispersedparticles appeared to be covered with a thick coating. This alsoappeared to be true at interfaces in general within the film samples

Examination of the liquid formulation used to make the films, after itwas allowed to sit, showed physical separation with at least two phases.One appeared to be an opaque gel-like substance surrounded by a liquidphase which appears to be of lower viscosity. This appears to be due toa syneresis effect.

What is claimed is:
 1. A multilayer soluble film made by deposit, comprising: a first soluble layer not containing a pharmaceutical active agent; and a second soluble layer provided on the first-soluble layer by depositing a solution comprising materials forming the second soluble layer without direct mechanical intervention to form the solution into a film on the first soluble layer, the second-soluble layer containing at least one pharmaceutical active agent and having a surface area different than a surface area of the first soluble layer, wherein the first soluble layer is a mucoadhesive layer or a slowly dissolving backing layer.
 2. The multilayer soluble film according to claim 1, wherein the first soluble layer is a mucoadhesive layer.
 3. The multilayer soluble film according to claim 1, wherein the first soluble layer is a slowly dissolving backing layer.
 4. The multilayer soluble film according to claim 3, wherein the second soluble layer has a mucoadhesive property.
 5. The multilayer soluble film according to claim 1, wherein at least one of the first and second layers has a mesomorphic phase.
 6. The multilayer soluble film according to claim 1, wherein the second soluble layer has a surface area smaller than a surface area of the first-soluble layer.
 7. The multilayer soluble film according to claim 1, wherein the second soluble layer has a surface area larger than a surface area of the first-soluble layer. 